Review ArticleReview
Open Access

Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine

Lina Hu, Xuanye Zhang and Shengbing Zang
Cancer Biology & Medicine September 2024, 21 (9) 754-768; DOI: https://doi.org/10.20892/j.issn.2095-3941.2024.0132

Abstract

Genome sequencing has revealed frequent mutations in Ras homolog family member A (RHOA) among various cancers with unique aberrant profiles and pathogenic effects, especially in peripheral T-cell lymphoma (PTCL). The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type, thereby leading to different functional and biological properties, which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors. However, the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated. Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways. The promising potential of targeting RHOA as a therapeutic modality is also outlined. This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

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Introduction

A peripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous mature T-cell lymphoma with a poor clinical outlook that accounts for 10%–15% of non-Hodgkin’s lymphomas1–3. Recent advances in high-throughput genomic studies and gene expression profiling have provided new insight into the pathogenesis, mutational landscape, and molecular biology of PTCLs4. Precise elucidation of the molecular background has revealed new therapeutic targets.

Gene sequencing has identified frequent hotspot mutations of Ras homolog family member A (RHOA) in a variety of human malignancies, including T- and B-cell lymphomas [approximately 1%–20% in diffuse large B-cell lymphoma (DLBCL5–7), 6%–10% in Burkitt’s lymphoma6,7, and 0% in mantle cell and Hodgkin lymphomas7,8] and other solid tumors with the occurrence in PTCL predominating and specifically affecting angioimmunoblastic T-cell lymphoma (AITL)9–13. RHOA is a small GTPase that was originally described as a key regulatory molecule linked to molding of the cytoskeleton14. The Rho family of GTPases consists of 22 members that have an essential role in T cell maturation and differentiation, negative and positive selection, and T-cell development and activation to maintain T-cell homeostasis15. The activities of most Rho GTPases are precisely regulated by a molecular switch comprising guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine dissociation inhibitors (GDIs)16, cycling between the GTP-bound active and inactive conformations to activate downstream effector proteins that regulate the cytoskeleton and stimulate physiologic actions17.

In recent years the RHOA oncogene has been shown to be involved in acquiring all the hallmarks of cancer18. RHOA has long served as a focal point for crosstalk between diverse tumorigenic signaling pathways. For example, RHOA synergizes with tet methylcytosine dioxygenase 2 (TET2) to promote transformation of AITL, but RHOA also has a direct role in tumorigenesis. Overexpression of activated RHOA regulates malignant transformation of tumor cells in vivo and is associated with tumor invasion and migration18,19. Notably, the distribution of mutation sites and hotspots in RHOA varies with tumor type, even leading to functional discrepancies10,13, thereby providing new insight into the molecular pathogenesis and potential targeted therapies against diverse neoplasms.

We retrieved approximately 40 publications involving RHOA mutations in T-cell lymphomas. Fifteen studies conducted full-length sequencing of RHOA, 13 of which demonstrated the diversity of RHOA mutations10,11,13,20–30. The p.Gly17Val (G17V) residue is the most frequently mutated RHOA site. Numerous uncommon and discrete mutational hotspots at other residues, such as C16R, K18N, and T19I, have also been identified. In this review we present the recent advances in the pathogenic role of RHOA in PTCLs with a focus on the complexity of prominent mutant loci of RHOA in the three subtypes [AITL, PTCL-not otherwise specified (PTCL-NOS), and adult T-cell leukemia/lymphoma (ATLL)]. We also discuss the implications of these abnormalities in clinical practice and outline the role of personalized pharmacotherapy in patients with PTCL.

RHOA mutations in PTCLs

Mutation profile of RHOA in various subtypes of PTCLs

Over recent years, genomic and transcriptomic studies have gradually reinforced our clarity on PTCL drivers and contributed to the perception of molecular vulnerability. RHOA mutations are less prevalent in B-cell lymphomas compared to many T-cell lymphomas in which RHOA is the hallmark mutation31. AITL and PTCL-NOS are the most common PTCLs in which recurrent somatic RHOA mutations were first11,25. RHOA mutations are also prevalent in ATLL and have unique features compared to other T-cell lymphomas10,32. In addition, RHOA mutations have been reported in some nodal PTCLs with the T follicular helper (TFH) phenotype (PTCL-TFH) and follicular T-cell lymphoma (FTCL)23,29. In addition, RHOA mutations are rarely identified in other subtypes of PTCL. RHOA mutations in different PTCL subtypes may have unique hotspot sites and distribution characteristics that influence functional and biological properties, which may provide clues to the mechanisms underlying tumorigenesis in different types of tumors.

RHOA mutation sites are not restricted to G17V and promote AITL and PTCL-NOS progression in a negative fashion

AITL and PTCL-NOS are highly aggressive groups of PTCLs. AITL is derived from TFH, with distinctive genomic aberrations and a dismal clinical prognosis, whereas PTCL-NOS exhibits extreme histologic and immunophenotypic heterogeneity and lacks specificity33. Notably, PTCL-TFH is a PTCL subset classified as NOS with a TFH cell phenotype, which may account for the similar molecular profile to AITL34. The G17V mutation in RHOA appears in patients with at least two positive surface markers for TFH and is highly specific for PTCL-TFH28. RHOA harbors the highest mutation rate in AITL (detected in 50%–70% of AITL patients11,25,27,31,35) and 14.6%–25% occurring in PTCL-NOS patients28,36. However, the majority of RHOA mutations encode p.G17V and the probability can reach 75%37. Moreover, it has been reported all AITL patients have been a single G17V mutation in RHOA38. According to our statistics of RHOA sequencing cases in published studies, in addition to RHOA G17V, multiple RHOA exon 2 mutations in AITL mainly involve p.K18N and p. F25L13,27,30, whereas RHOA exon 2 mutations in PTCL-NOS primarily include p.C16* and p.F25L13. Herein we summarize the diverse nature of RHOA mutation sites in PTCL (Figure 1A, B).

Figure 1
Figure 1

Discrete positional distribution and amino acid substitution types of RHOA mutations in PTCL. (A) In AITL, RHOA mutations mostly encode p.Gly17Val (G17V), which occurs in the highly conserved GTP-binding structural domain, and p.K18N and p.F25L. (B) In PTCL-NOS, the RHOA mutation site is like that in AITL, mainly involving site 17 but with a much lower frequency of G17V mutations. (C) RHOA mutations are homogeneously distributed in PTCL-TFH and FTCL and involve both the uncommon L18G, Y34Y, and A49T residues in one FTCL patient. (D) In ATLL, RHOA mutation shows a unique pattern that is widely distributed throughout the coding region with the C16R mutation as the most prevalent. AITL, angioimmunoblastic T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; PTCL-TFH, peripheral T-cell lymphomas with T follicular helper phenotype; FTCL, follicular T-cell lymphoma; ATLL, adult T-cell leukemia/lymphoma.

The RHOA mutation sites in AITL and PTCL-NOS are relatively homogeneous, suggesting that RHOA G17V has a crucial role in ontogeny and proliferation. G17V alterations occur in the highly conserved RHOA GTP-binding structural domain. Overexpression of RHOA is a common feature of multiple malignancies18. Surprisingly, structural modeling and molecular simulations have revealed that RHOA G17V lacks GTPase activity, much like the dominant-negative RHOA mutant with T19N11,25,31. This loss-of-function mutation disrupts RHOA binding to GTP/GDP and interferes with RHOA signaling and activation of downstream effector proteins, promoting cell proliferation and invasiveness in a negative fashion31. Moreover, RHOA G17V affects the ability of endogenous and exogenous wild-type RHOA to bind to GTP and promote PTCL pathogenesis11. In addition to the most common RHOA G17V loss-of-function mutation in AITL and PTCL-NOS, other RHOA mutants have been reported in PTCL (Table 1). Mutations in amino acids at other sites of RHOA, although much less frequent than at site 17, show opposite pathogenic effects, some of which are functionally enhanced mutations, such as RHOA C16R and RHOA K18N24,27. In general, multiple mutations in RHOA provide clues to elucidate the potential molecular pathogenesis of PTCL.

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Table 1

Distribution of various RHOA mutation types in PTCL

RHOA C16 mutation is a hotspot and facilitates ATLL in a dominant-positive fashion

ATLL is a PTCL subtype with adverse biological behavior. ATLL is caused by the human T-lymphotropic virus type 1 (HTLV-1) retrovirus39. In addition to viral infections, the development of ATLL requires additional genetic accumulation or epigenetic events40,41. To date, however, the genetic and molecular alterations associated with ATLL have not been fully defined. Whole genome sequencing has shown recurrent RHOA mutations in 15% of ATLL patients10,24. RHOA mutations in ATLL differ from the distribution characteristics of clustering at the G17V site in AITL and PTCL-NOS by showing a unique widespread distribution pattern throughout the coding region10. RHOA mutations in ATLL are significantly concentrated in the GTP-binding structural domain and show discrete mutational hotspots at residues C16, G17, and A161 with C16R mutation being the most prevalent (Figure 1D)10. Another noteworthy feature is the discrepancy in the functional role. Two newly identified RHOA mutants in ATLL (C16R and A161P) bind to GTP analogs more rapidly and increase the GDP/GTP exchange rate. In addition, C16R and A161P mutants enhance the intrinsic RHOA function and activate downstream effector molecules in a dominant-positive fashion10. The findings are inconsistent with the fact that RHOA mutations in AITL always involve G17 residues and act as negative factors. Therefore, RHOA exhibits multiple mutational patterns and roles in various tumors with gain- and loss-of-function mutations serving as molecular mechanisms promoting lymphoma pathogenesis (Table 2).

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Table 2

Mutational position and functional alterations of RHOA in various PTCL subtypes

The opposing biochemical activity of RHOA mutants observed in ATLL may be explained with respect to cell phenotype and profile. Based on surface marker and immunohistochemical analyses, ATLL cells with gain-of-function mutations that activate C16R and A161P contain a regulatory or effector T-cell phenotype. ATLL cells with inactivated G17V, however, have a memory T-cell phenotype10,32. Multiple RHOA mutation patterns reflect the different origins of ATLL cells, which is one interpretation of RHOA mutation diversity. Furthermore, RHOA is a key molecule of T-cell receptor (TCR) signaling that strictly regulates the development of T cells and proper assembly of early TCR signaling complexes during the tumorigenic phase42. Changes in TCR signaling affect the selection of CD4+ or CD8+ T cells and differentiation of specific T-cell subpopulations43, which are essential for the induction of forkhead box P3 and commitment of Treg cell lineage44,45. Therefore, altered downstream signaling of TCR caused by multiple mutations in RHOA may also lead to differences in the ATLL cell immunophenotype.

RHOA G17V contributes to PTCL pathogenesis through gene crosstalk and aberrant activation of downstream signaling pathways

RHOA mutations are most common in AITL and PTCL-TFH, in which mutations nearly always affect G17 residues and are accompanied by co-existing TET2 mutations11,25. RHOA G17V has an inhibitory role in RHO signaling and promotes PTCL pathogenesis by negatively inhibiting the binding of wild-type RHOA to GTP11,25. Somatic co-mutations of TET2 and RHOA are observed in 60%–70% of patients with AITL. The synergistic effect leads to an increased rate of AITL epistasis11,25. Indeed, RHOA mutations in T-cell lymphomas are always associated with abnormalities in epigenetic regulators, such as TET2, DNA methyltransferase 3 alpha (DNMT3A), and mitochondrial isocitrate dehydrogenase II (IDH2)46,47. In mouse models, cooperative mutations in TET2 and RHOA G17V lead to abnormal proliferation and differentiation of CD4+ T cells by interfering with FoxO1 expression, inducing TFH cell specification and an increased prevalence of lymphomagenesis48,49. Mice with a TET2 deletion combined with an RHOA mutation are able to spontaneously develop AITL, whereas mice lacking TET2 in T cells only do not develop AITL50. These findings confirm the multistep model and the second strike theory of AITL pathogenesis, which was reviewed in our previous work51. In contrast, TET2 mutations are less frequent in ATLL, accounting for only 17% of RHOA variant cases10. Moreover, DNMT3A and IDH2 mutations, which are prevalent in AITL, are only detected in a minority of ATLL cases10, implying that RHOA has an inconsistent role in the mechanism underlying lymphomagenesis of these PTCL types. However, it has also been recently shown that IDH2 and TET2 co-mutations impair TCR signaling and promote the development of AITL52.

In addition to the combined interaction with epigenetic abnormalities, RHOA G17V increases the frequency and decreases the latency of T-cell lymphoma, which confirms its singular role as an oncogene in developing lymphomagenesis53. RHOA G17V is involved in the downstream activation of TCR and is an important mediator of T-cell activation15. Targeted deep sequencing of the AITL genomes rich in TCR signaling elements have revealed that 60% of these cases are affected by RHOA mutations and most are dominant-negative G17V variants, with only three cases being new K18N variants27. In addition to the highly recurrent RHOA mutations, Vav guanine nucleotide exchange factor 1 (VAV1) mutations have been identified27. VAV1-deficient T cells are defective in TCR-induced intracellular calcium flux, activation of extracellular signal-regulated kinase, and transcription factor nuclear factor kappa beta (NF-κB)54, with oncogenic VAV1 signaling having a driving role in malignant transformation of T cells55. Using high-throughput screening, VAV1 has been identified as a G17V RHOA-specific binding chaperone. Activation of RHOA-VAV1 signaling enhances phosphorylation of 174Y, thereby leading to aberrant activation of VAV1 and consequently enhancing its adapter function56. This activation of RHOA-VAV1 signaling may trigger phosphorylation of PLCγ1 and the transcriptional activity of NFAT, which leads to accelerated TCR signaling in vitro56. Enhancement of TCR signaling induces the proliferation of T-cell neoplasms. Indeed, the G17V RHOA-VAV1 axis may provide a new therapeutic target for AITL.

Patients affected by RHOA G17V have a characteristic tendency towards differentiation into the TFH lineage. In vitro studies have revealed the underlying mechanism by which RHOA G17V induces TFH lineage specification and AITL transformation by upregulating inducible co-stimulatory factors (ICOS) and increasing phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase signaling48,53. Blockade of the ICOS-PI3K-mammalian target of rapamycin (mTOR) signaling pathway provides an innovative potential strategy for targeting RHOA G17V therapy. In addition, a major pathway downstream of PI3K signaling is the Akt-mediated inactivation of forkhead box O (FOXO) family of transcription factors57. ICOS signaling relaxes the restriction of TFH cells with reduced dependence of ICOS ligands by inactivating the transcription factor, FOXO1, and maintains the differentiation of TFH cells by inducing the guidance of the transcriptional repressor, Bcl658,59. The RHOA G17V mutation in mature mice interferes with FoxO1 expression and causes abnormal immune responses49. Furthermore, co-stimulation of ICOS is critical in maintaining the TFH phenotype by downregulating the zinc finger transcription factor, Krüppel-like factor 2 (Klf2), via FOXO160. Thus, the PI3K-AKT-FOXO1 signaling pathway has an irreplaceable role in controlling FTH lineage commitment and is a downstream pathway affected by RHOA G17V mutations. Notably, RHOA has been shown to be a “central” regulator linking the TCR and PI3K signaling pathways, possibly balancing T-cell proliferation by activating the VAV1-RAC1-RHOA-ROCK-PTEN-PI3K-AKT route, where RHOA mutations can derail the balance31. Other pathways significantly associated with RHOA G17V, such as KRAS, the alternative NF-κB pathway, and the RAC1 pathway, have also been reported to be closely associated with PTCL pathogenesis61. These observations suggest that RHOA G17V regulates the homeostasis of T-cell proliferation through multiple mechanisms and pathways of action, while RHOA mutations have a separate driving role as oncogenes in the hyperactivation of oncogenic pathways and pathogenesis of T-cell lymphoma (Figure 2). However, in contrast to RHOA G17V, other types of RHOA mutations, such as C16A, C16R, K18N, and T19I, lack definitive pathogenic mechanisms. How loss-of-function mutations at other loci and gain-of-function mutations that mainly occur in ATLL cause PTCL is unclear and deserves explicit resolution.

Figure 2
Figure 2

RHOA G17V disrupts the proliferative balance of T cells by crosstalk with additional genes and aberrant activation of downstream signaling pathways. In peripheral T-cell lymphoma, TET2 loss induces the onset of hematopoietic abnormalities as an initiating strike in naive T cells, while RHOA G17V mutation is a secondary hit. The cooperation of G17V with its specific binding partner VAV1 is involved in the downstream activation of TCR by enhancing phosphorylation of 174Y, triggering the phosphorylation of PLCγ1 and the transcriptional activity of NFAT. Furthermore, oncogenic VAV1 signaling was able to promote the malignant transformation of T cells by inducing increased intracellular [Ca2+] flux, ERK MAP kinase, and transcription factor NF-κB activation. In addition, RHOA G17V induces TFH lineage specification through upregulation of the ICOS-PI3K-AKT-mTOR signaling pathway and inactivation of the transcription factor FOXO1. TCR, T-cell receptor; LCK, lymphocyte-specific protein-tyrosine kinase; ZAP70, zeta chain of T-cell receptor associated protein kinase 70; GRB2, growth factor receptor-bound protein 2; SOS, son of sevenless; SLP76, SH2 domain-containing leukocyte protein of 76 kDa; GADS, GRB2-related adaptor protein; ITK, interleukin-2-inducible T-cell kinase; PLCγ1, phospholipase Cγ1; VAV1, vav guanine nucleotide exchange factor 1; PIP2, PLCγ1 hydrolyzes phosphatidylinositol-4,5-biphosphate; IP3, inositol-1,4,5-trisphosphate; NFAT, nuclear factor of activated T cells; DAG, diacylglycerol; PKC, protein kinase C; CARD11, caspase recruitment domain family member 11; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; NF-κB, nuclear factor-kB; AP1, activator protein 1; ICOS, inducible co-stimulatory factor; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; FOXO1, forkhead box O1.

Prognostic significance of RHOA in PTCL

Several studies have shown no difference in overall survival (OS) between patients with an ROHA G17V mutation and wild-type AITL paetients11,62–65, but ROHA G17V mutant patients appear to possess worse progression-free survival (PFS) and a lower response rate to first-line chemotherapy62.

Recently, RHOA non-silent mutations have been included in m7-ATLPI, a risk model for ATLL, as a poor prognostic correlate66. The m7-ATLPI model combines clinical risk factors and the mutation status of seven genes, including TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3, to stratify the prognostic superiority and overall length of survival after chemotherapy in patients with ATLL and to help low-risk patients avoid overtreatment. The poor prognostic impact of RHOA mutations may provide insight into targeted therapies for ATLL.

Targeting RHOA and its downstream signaling network provides strategies for individualized therapy

Members of the RHO GTPase family have a central role in many cellular processes and RHOA variants exert a substantial impact on the pathogenesis of PTCL owing to high mutation rates. Efficient and specific pharmacologic exploration of RHOA and its associated effective signaling are considered an attractive field of study for innovative cancer therapy. However, little progress has been made in lymphoma research using small molecule inhibitors of RHOA in contrast to the more lucid situation involving RHOA-targeted agents studied in solid tumors, such as breast and gastric cancers67–69. Only in vitro experiments have shown that RHOA G17V activates the PI3K-AKT-mTOR signaling pathway and PI3K inhibitors effectively inhibit RHOA G17V-induced cell proliferation, which established the experimental basis for blocking aberrant activation of the downstream RHOA G17V signaling pathway48,49,53. We reviewed a comprehensive profile of potential targets for RHOA and the signaling network, focusing on multi-kinase inhibitors, blockers of the PI3K pathway, and inhibitors of the mTOR pathway (Table 3).

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Table 3

Clinical efficiency of drugs targeting RHOA and its downstream signaling network in PTCL

Multi-kinase inhibitors

Dasatinib, an orally administered small molecule tyrosine kinase inhibitor (TKI), inhibits multiple kinases, including BCR-ABL1, c-KIT, platelet-derived growth factor receptor-β, ephrin receptor A2, and the SRC family (e.g., SRC, LCK, YES, and FYN)83. Dasatinib has been approved by the US Food and Drug Administration (FDA) for treating chronic myeloid leukemia in adults and pediatrics, while the efficacy in lymphoma is still under investigation84. In an in vitro assay, dasatinib and PP2, a pan-Src kinase inhibitor, inhibited G17V RHOA-induced VAV1 phosphorylation and aberrant signaling in a dose-dependent fashion56. Nguyen et al. used dasatinib to treat mice with TET2 mutations accompanied by G17V RHOA expression and reported that dasatinib prolonged survival by inhibiting hyperactivated TCR signaling70. Nguyen et al.70 also tested the efficacy of dasatinib in a phase I clinical trial, including five patients with relapsed/refractory (R/R) AITL, two of whom achieved a partial response (PR) and two responded with progressive disease (PD) at trial termination70. This study provided in vivo evidence that dasatinib blocks the G17V RHOA-VAV1-TCR axis and that high response rates are observed by application in patients with AITL. In addition, dasatinib has been used in multiple phase I/II clinical trials for the treatment of R/R T-cell lymphoma (NCT00608361, NCT01609816, NCT01643603, and NCT00550615). In NCT00550615, the objective efficiency rate was 29.2%, indicating a promising outlook for applying dasatinib in T-cell lymphoma.

PI3K inhibitors

PI3K is a lipid kinase involved in intracellular signaling that promotes survival, proliferation, and differentiation of malignant hematopoietic cells through multiple pathways85. Initially, PI3K inhibitors have shown excellent efficacy in patients with relapsed indolent non-Hodgkin’s lymphoma86, and recent studies have shown antitumor activity against PTCL87.

Duvelisib (IPI-145)

Duvelisib, which is also known as IPI-145, is an oral drug that is a dual inhibitor of PI3K-δ and PI3K-γ. A phase I clinical study evaluated the maximum tolerated dose (MTD) of duvelisib in 210 patients with advanced R/R hematologic malignancies, including 16 patients with PTCL and 18 patients with primary treatment71. Patients received an oral dose of duvelisib twice daily over a 28-day cycle until disease progression or unacceptable toxicity with a final MTD of 75 mg twice daily; the 25 mg twice-daily dose showed optimal efficacy. One-half of PTCL patients had a response, with three patients exhibiting a complete response (CR) and five a PR. Moreover, an interim analysis of the phase 2 Primo trial revealed an excellent performance with duvelisib in patients with R/R PTCL (especially AITL) with an overall response rate (ORR) of 66.7% and a CR of 47.6%, suggesting that the therapy is superior to currently available treatment options72.

In addition, the combination regimen with duvelisib demonstrated reliable activity and safety against R/R PTCL in multiple pre-clinical and clinical trials78,79,88. Moskowitz et al. conducted a multicenter parallel phase I trial with duvelisib in combination with romidepsin [arm A (12 patients with TCL)] or bortezomib [arm B (17 patients with TCL)], all of whom exhibited favorable activity with an ORR > 50% in both arms78. Serious adverse events (SAEs) associated with the study drug in both groups included fatigue, an elevated aspartate aminotransferase (AST) level, and pneumonia. The incidence of elevated AST/alanine transaminase (ALT) levels was limited, reflecting relatively good tolerability of the combination. Another group of duvelisib in combination with romidepsin also achieved promising results in 22 patients with R/R PTCL, with an ORR of 55% and CR of 27%79. Lastly, a phase I dose escalation study of the combination of duvelisib and oral azacitidine (CC-486) is ongoing to determine MTD in patients with lymphoid malignancies89. Measuring the degree of phosphorylation of AKT in peripheral CD3+ T cells will serve as a biomarker to assess efficacy. Indeed, this study may pioneer the use of duvelisib in combination with hypomethylating agents. In conclusion, duvelisib demonstrates promising clinical activity and an acceptable safety profile in monotherapy and combination therapy for R/R PTCL, which may be a potential therapeutic advance that warrants further evaluation in relatively large studies.

Tenalisib (RP6530)

Tenalisib (also known as RP6530) is a novel, highly specific, and dual inhibitor of PI3Kδ/γ, which has achieved positive results in clinical studies for PTCL therapy in recent years. Currently, only one phase 1/1b clinical trial involving tenalisib monotherapy in R/R TCL has published final results73. A total of 58 patients with TCL were enrolled, including 28 with PTCL and 30 with CTCL. Efficacy assessment showed an ORR of 46%, with 47% for PTCL (including 3 and 4 patients with CR and PR respectively) and 45% for CTCL. The overall median duration of overall response (DOR) was 4.91 months. The DOR for PTCL patients was 6.53 months. Treatment-related grade ≥ 3 AEs occurred with an elevated ALT/AST levels (21%), skin rash (5%), and hypophosphatemia (3%). Given that these events were reversible and manageable by withholding the study drug, the safety profile of tenalisib was considered acceptable. The security and favorable clinical activity of tenalisib were also confirmed in the subgroup analysis of the trial90,91.

Combinations of tenalisib with other drugs are also underway, mainly with romidepsin. In a phase I/II open-label multicenter study involving tenalisib in combination with romidepsin, the response of 12 patients with R/R PTCL (5 and 6 with PTCL-NOS and AITL, respectively) was evaluated after dosing, with a CR of 40% in patients with PTCL-NOS and 66.7% in patients with AITL80. The disease control rate reached 91.7%, which was an unexpected outcome. Overall, tenalisib showed excellent clinical activity and was safely tolerated in patients with R/R PTCL. Given the low incidence of toxicity with tenalisib, the safety profile further supports broad clinical application.

Linperlisib (YY-20394)

Linperlisib is a novel PI3Kδ-selective inhibitor, which has previously demonstrated excellent efficacy in B-cell lymphoma92,93. Updated results from a phase Ib clinical trial of linperlisib for R/R T-cell lymphoma have been recently published74. The trial enrolled 43 patients with R/R PTCL, including 17 with PTCL-NOS and 16 with AITL. Analysis of the results showed an ORR of 61% and a CR rate of 38%, with AITL patients achieving an ORR of 81%. The median progression-free survival (PFS) and median DOR were 11.8 and 11.1 months, respectively.

Treatment-related adverse events (TRAEs) were observed in 39 patients (91%), the most common of which was neutropenia (65%). Grade ≥ 3 AEs (≥ 5%) were neutropenia (21%), pneumonia (12%), and hypertriglyceridemia (7%). Based on the current data, the safety and efficacy of linperlisib are still promising. Phase II clinical trials involving linperlisib for treating R/R T-cell lymphoma are enrolling in the US and Italy.

Inhibitors of mTOR

The mTOR target is a serine/threonine protein kinase that integrates inputs from various upstream pathways, including the PI3K/AKT pathway. mTOR is a major regulator of cell growth and metabolism94. mTOR is constitutively activated in malignant B- and T-cell hematopathology and is responsible for TCL proliferation, which has become an important focus of therapeutic interventions in cancer95. mTOR inhibitors include rapamycin, everolimus (RAD001), and temsirolimus (CCI-779). Rapamycin efficiently inhibits mTOR, which suppresses tumor T cell proliferation and mTORC1/296.

Everolimus is an inhibitor of mTORC1. The first phase II clinical trial demonstrating significant antitumor activity of everolimus in patients with relapsed TCL has shown an overall efficacy rate of 44%, with the highest efficacy rate of 75% in patients with PTCL-NOS75. Subsequently, Kim et al. conducted phase I and II trials based on the promising results of the combination of everolimus and CHOP for PTCL and utilized everolimus as a first-line agent for newly diagnosed PTCL77,97. Different PTCL subtypes have shown variable CR rates, with AITL and PTCL-NOS accounting for the top 2 efficacy rates [100% (3/3) and 63% (12/19)], respectively. Kim et al.77,97 reported that application of everolimus in patients with PTCL significantly improves the response rate to CHOP, but was inferior to the combination of alemtuzumab and CHOP in another study98. In addition, the relatively short response time indicated that this combination is of limited value, which requires the investigation of novel combination regimens. Recently, a clinical trial involving everolimus in combination with gemcitabine has reported final results with an ORR of 55.6% (n = 10) and a CR rate of 50% in 18 patients with R/R PTCL81. In general, given the low response rate and short duration of everolimus monotherapy and its combinations in patients with R/R PTCL, innovative modalities to enhance efficacy are necessary.

Other possibilities

A recent phase I trial investigating the side effects and optimal dose of an anti-ICOS monoclonal antibody (MEDI-570) for treating patients with PTCL follicular variant or angioimmunoblastic T-cell lymphoma is underway (NCT02520791), which represents the emerging applications of immunotherapy in PTCL99. Other pathways that are differentially activated in PTCL owing to RHOA mutations, such as KRAS, the NF-κB pathway, and the RAC1 pathway, are also associated with RHOA-targeted therapy. Bortezomib, a protease inhibitor with inhibitory activity to NF-κB, has been applied in clinical trials to treat PTCL.

A phase II clinical trial in 15 patients with R/R ATLL has been conducted to evaluate the efficacy and safety of bortezomib, showing an ORR of 6.7% and PFS of 38 days76. During this course, 80% of patients had ≥ 1 grade 3/4 AEs. After an overall analysis, single-drug activity did not appear to have promising prospects for this group of patients. In contrast, the combination of bortezomib with the pan deacetylase inhibitor, panobinostat, has shown effects higher than the single agent82. A total of 25 patients with R/R PTCL (9 and 8 with PTCL-NOS and AITL, respectively) were included in this study, with an encouraging ORR of 43% and CRR of 21.7%.

Conclusions

RHOA is arguably an extensively studied member of the Rho-GTPase protein family and has long been implicated in the heterogeneity of PTCL. In this review we comprehensively summarized the variegated mutation landscape and hotspots of RHOA in PTCL [mainly for the three subtypes (AITL, PTCL-NOS, and ATLL)] and revealed the unexpected complexity of mutation sites involving more than just Gly17 residues in RHOA. Aberrant activation of downstream signaling pathways by RHOA and involvement in multi-step genetic events will provide clues to understand the pathogenesis and overcome the impediments to PTCL therapy. Potential treatment candidates, such as blocking the TCR and ICOS-PI3K-mTOR pathways or targeting phenotypic surface markers, may improve clinical outcomes in patients with RHOA mutations and PTCL. Whether the RHOA G17V mutation can be used as a therapeutic marker for the efficacy of PI3K inhibitors applied to patients with AITL is a question worth exploring in the future. Targeting specific molecular abnormalities will unearth promises for individualized pharmacotherapy.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Lina Hu, Xuanye Zhang, Shengbing Zang.

Collected the data: Lina Hu, Xuanye Zhang.

Contributed data or analysis tools: Lina Hu, Xuanye Zhang.

Performed the analysis: Lina Hu, Xuanye Zhang, Shengbing Zang.

Wrote the paper: Lina Hu, Xuanye Zhang, Shengbing Zang.

Acknowledgements

The authors would like to thank Professor Suxia Lin for her insightful comments and contributions to editing the manuscript.

Footnotes

  • ↵*These authors contributed equally to this work.

  • Received April 10, 2024.
  • Accepted June 20, 2024.

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