Inflammatory signaling in targeted therapy resistance: focus on EGFR-targeted treatment

Targeted therapy in cancer

With advances in sequencing technologies, targeted therapy has emerged as a viable and pivotal approach in cancer treatment. One key advantage of targeted therapy is the personalized application. By identifying genetic mutations, aberrant signaling pathways, or other molecular characteristics unique to each patient’s tumor, clinicians can tailor treatment regimens to target these specific vulnerabilities. Specifically, genetic mutations give rise to novel proteins distinct from the wild-type counterparts. These proteins drive tumor cell survival and reliance on mutated genes, making the proteins targetable and druggable. Currently, a variety of targetable genetic aberrations occur in genes encoding kinases (e.g., BCR-ABL, EGFR, HER2, FGFR1/2/3, PDGFR, VEGFR, ALK, MET, NTRK, RET, and ROS1) and downstream signaling effectors (e.g., BRAF, KRAS, MEK1/2, and PI3KCA), tumor suppressors (e.g., BRCA1/2 and TP53), and chromatin modifiers (e.g., IDH1/2 and EZH2)¹. Most of these mutations have corresponding targeted therapies available for clinical use (Table 1). In essence, the rapid advances in targeted therapy are revolutionizing cancer treatment by exploiting specific genetic aberrations for personalized medicine and improved patient outcomes.

Challenges in targeted therapy resistance

Targeted anti-tumor therapy has revolutionized cancer treatment due to its significant efficacy and low toxicity profile. However, drug resistance remains an inevitable challenge, often emerging post-treatment. Tumor cells tend to develop acquired resistance during therapy because of new genetic mutations. For example, the development of resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancers often involves second-site EGFR T790M mutations, which renders the original EGFR TKIs ineffective². Similarly, resistance to BRAF inhibitors in melanoma leads to the emergence of various new mutations, such as KRAS mutations (20%), BRAF^V600E/K amplifications (13%), and MEK1/2 mutations (7%)³. Additionally, growing evidence suggests that non-genetic adaptive changes also contribute to tumor resistance. For example, alterations in the β-catenin-LEF1 and YAP1 signaling pathways have been implicated in melanoma resistance to MAPKi, resulting in reduced apoptosis and enhanced resistance⁴. Moreover, the tumor microenvironment (TME) assumes a critical role in nurturing resistance mechanisms. Various growth factors and cytokines originating from the neighboring TME contribute to drug resistance. Indeed, drug resistance creates a protective barrier against therapeutic interventions⁵. Consequently, dissecting the intricate crosstalk within the TME reveals latent vulnerabilities ripe for exploitation to augment treatment efficacy. Typically, targeted therapy triggers activation of bypass pathways, circumventing the original pathway targeted for cancer cell death. The mechanisms underlying this resistance are unclear and warrant further exploration in corollary studies.

Inflammatory pathways in targeted therapy resistance

The TME is comprised a complex network of immune cells, stromal cells, and signaling molecules that influence cancer progression and treatment response. Targeted therapies aimed at impeding cancer cell survival induce polarization and dysfunction of immune cells within the TME, fostering therapeutic resistance. Recent studies highlight the dynamic interplay between immune and cancer cells in the context of targeted therapy resistance. BRAF inhibition recruits and reprograms macrophages into an M2 phenotype in melanoma mouse models, which enhances macrophage-derived secretion of VEGF. This secretion subsequently reactivates ERK in melanoma cells, leading to therapeutic resistance⁶. Additionally, the multi-RTK inhibitor sorafenib impairs dendritic cell function and the induction of antigen-specific T cells in mouse models⁷. Moreover, inflammatory cytokines and chemokines released by immune cells activate survival pathways in cancer cells, thereby enhancing the resistance to targeted agents⁸. In addition to immune cell-mediated mechanisms, aberrant activation of inflammatory signaling pathways within tumor cells has been linked to resistance against targeted therapies. Our previous investigations showed that targeting EGFR with inhibitors in glioblastoma and lung cancer upregulates tumor necrosis factor (TNF) signaling. This upregulation precipitates a TNF-driven adaptive response that confers resistance to EGFR inhibition. Moreover, the nuclear factor-kappa B (NF-κB) pathway, a pivotal regulator of inflammation, is upregulated in a TNF-dependent manner, which contributes to the development of EGFR inhibition resistance. Similarly, our group reported that activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which is induced by interferon type I (IFN-I), is associated with resistance to EGFR TKIs (Figure 1A). These findings highlight the critical role of targeting inflammatory signaling pathways to overcome therapeutic resistance^9–12.

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Figure 1

Mechanisms of resistance to targeted therapy mediated by inflammatory signals and immune cells. (A) Resistance mechanism induced by upregulation of TNF and IFN in EGFR-targeted therapy. TNF is rapidly activated in response to EGFR inhibition and plays a crucial role in resistance to EGFR-targeted treatments. Upon TNF binding to TNFR1, IKK is recruited and activated by the TNFR1 complex. The activated IKK phosphorylates IκB, which is then rapidly degraded by polyubiquitination. The degradation of IκB releases NF-κB, allowing NF-κB to translocate into the nucleus and promote the transcription of numerous NF-κB target genes. Nuclear NF-κB binds to the promoter of TNF, increasing TNF expression in a feed-forward loop. Many of these NF-κB target genes have anti-apoptotic and pro-survival functions. Additionally, type I interferon (IFN-I) is upregulated in response to EGFR inhibition. RIG-I is strongly induced by EGFR inhibition, leading to the ubiquitous expression and activation of TBK1. The ubiquitin ligase, TRIM32, associates with TBK1 upon EGFR inhibition and is necessary for K63-linked ubiquitination and TBK1 activation. Inhibiting mutant EGFR triggers IFN-I upregulation via the RIG-I-TBK1-IRF3 pathway. STAT1 activation by IFN-I promotes cell survival and therapeutic resistance in the context of EGFR inhibition. (B) Immune cells or inflammatory factors in the TME resist targeted therapy in various ways. BRAF inhibitors (BRAFi) paradoxically activate the mitogen-activated protein kinase (MAPK) pathway in macrophages in BRAF-mutant melanomas, leading to the production of VEGF, which reactivates the MAPK pathway in melanoma cells and promotes cell growth. Additionally, inflammatory factors released from dying tumor and immune cells during targeted therapy may activate novel survival pathways in tumor cells, contributing to resistance to targeted therapy. TKIs, tyrosine kinase inhibitors; TNF, tumor necrosis factor; EGFR, epidermal growth factor receptor; TNFR1, tumor necrosis factor receptor 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IκB, inhibitor of NF-κB alpha; IKK, IκB kinase; IFN, interferon; RIG-I, retinoic acid-inducible gene I; TBK1, TANK-binding kinase 1; TRIM32; tripartite motif-containing 32; IRF3, interferon regulatory factor 3; STAT1, signal transducer and activator of transcription 1; VEGF, vascular endothelial growth factor; TME, tumor microenvironment.

Targeted therapies, by inhibiting pathways vital for cancer cell proliferation and survival, reduce tumor growth but may also induce inflammatory cell death. For example, inhibition of MEK, EGFR, or ALK pathways in lung cancer cell lines driven by these pathways results in pyroptotic cell death, which is characterized by GSDME cleavage¹³. The occurrence of inflammatory cell death often coincides with an escalation in pro-inflammatory cytokines, profoundly affecting both tumor cells and the immune microenvironment. This phenomenon fosters targeted drug resistance by circumventing oncogene addiction and rendering conventional targeted therapies ineffective (Figure 1B). Consequently, a comprehensive understanding of the regulatory mechanisms governing these pathways may offer novel insights and strategies to overcome targeted therapy resistance. This knowledge provides a crucial theoretical foundation for the further optimization and personalization of cancer treatment.

Overcoming inflammation-driven resistance to targeted therapy

The multifaceted targeting in cancer therapy presents significant potential for combination approaches. Currently, overcoming resistance originating from immune and inflammatory pathways within the tumor or its microenvironment presents a promising avenue through combination therapies. These approaches hold the potential for disrupting pro-survival signaling pathways and eliciting robust antitumor immune responses.

EGFR-activating mutations frequently occur in tumors. Our previous studies have revealed that the combined use of EGFR TKIs and TNF inhibitors significantly suppresses the growth of secondary resistant tumors. Furthermore, this combination therapy exhibits similar inhibitory effects on EGFR wild-type (EGFRwt) tumors, which are non-responsive to EGFR TKIs^11,12. Mechanistically, inhibition of EGFR signaling prompts tumor cells to activate the TNF pathway for cell survival and concurrent inhibition of the TNF pathway can eliminate the formation of this new dependency. Furthermore, tumor cells upregulate inflammatory signals, recruiting and hijacking immune cells within the TME, thereby fostering an inflammatory immune milieu. This process not only shapes the tumor cells to develop novel dependency pathways to bypass oncogene addiction but also hampers immune surveillance, rendering immune-cell-dependent targeted therapies ineffective. As the mechanisms of the TME unfold, the emergence of resistance to targeted therapies increasingly intertwines with immunotherapy. With successful trials of combined targeted therapies and immune checkpoint inhibitors (ICBs), numerous studies investigating combination therapies are underway. Clinical trials combining PD-1/PD-L1/CTLA-4 blockades with MAPK inhibitors, EGFR inhibitors, or BRAF and MEK inhibitors are being conducted in BRAF-mutant and wild-type melanoma^14–18. Targeted therapy combined with immunomodulatory or anti-inflammatory approaches appears to hold promise in overcoming resistance to targeted therapy in cancer. However, substantial research efforts are still required to elucidate the mechanisms underlying this phenomenon. The identification of predictive biomarkers associated with inflammation-induced resistance is imperative for accurate patient stratification and the development of personalized treatment strategies.

Discussion and perspectives

Targeted therapy has evolved rapidly, offering personalized treatment options for various malignancies. Recent advances, especially the approval of AMG510 (sotorasib) targeting KRAS (G12C)¹⁹, underscore the progress being achieved in targeted therapy. However, the critical challenge now is addressing acquired resistance to these therapies.

A key mechanism underlying resistance involves upregulation of alternative survival pathways that bypass the targeted mutations. Understanding how targeted therapies induce these compensatory pathways is crucial for overcoming resistance. While immune and inflammatory pathways have traditionally been associated with tumor suppression, the pathways also contribute to resistance. Inhibitors often trigger inflammatory responses that foster tumor cell survival by activating new dependency pathways. Furthermore, immune cells in the TME have a role in resistance formation, altering the immune landscape to support tumor cell evasion of targeted therapies. Thus, targeting inflammatory and immune signals presents a promising strategy for addressing resistance. Fortunately, antagonists targeting major inflammatory cytokines, such as TNF, IL-6, and IL-1, as well as chemokines or chemokine receptors, can be administered safely to patients with advanced-stage cancers⁸. These valuable preliminary studies may offer promising solutions to the issue of drug resistance in targeted therapy.

Addressing inflammation-driven resistance represents a formidable challenge in precision medicine, necessitating collaborative efforts across disciplines. Future research endeavors should focus on elucidating the dynamic interplay between inflammation, immune response, and therapy resistance at single-cell resolution. Integration of multi-omics data and computational modeling holds promise for identifying novel therapeutic targets and predictive biomarkers. Moreover, clinical trials should incorporate comprehensive molecular profiling to facilitate patient stratification and optimize treatment outcomes. Ultimately, a deeper understanding of the molecular mechanisms driving inflammation-mediated resistance will pave the way for the development of more effective therapeutic strategies and improve patient outcomes in diverse disease settings.

Author contributions

Conceived and designed the analysis: Zhihong Luo, Ke Gong.

Wrote the paper: Zhihong Luo, Ke Gong.