Targeting downstream signaling pathways of RAS as combination therapy

Targets	Inhibitors	Results	RAS protein	Cancers	Reference
MEK and PI3K	NVP-BEZ235 and ARRY-142886	Marked downregulation of PI3K, ERK and downstream signaling	KRAS	Lung cancer	¹⁰³
MEK and PI3K	PD0325901 and GDC-0941	Enhanced induction of apoptosis, inhibition of cell proliferation, and significant increase in tumor growth inhibition in xenograft models	KRAS	Breast cancer	¹⁰¹
MAPK and PI3K	PI103 and PD0325901	Significant increase of apoptosis after combined treatment	Total RAS	NSCLC	¹⁰⁴
MEK and PI3K	GDC-0973 and GDC-0941	Induction of biomarkers associated with apoptosis	KRAS	NSCLC, colorectal, prostate, and pancretic cancer	¹⁰⁰
MEK and mTOR	Selumetinib and AZD8055	Xenograft tumor regressions with growth inhibitions, lower phosphorylation of ERK1, S6P, and 4EBP, increasing apoptosis	KRAS	NSCLC and colorectal cancer	¹⁰²
MEK and AKT	MK-2206 and AZD6244	Improved disease control rate	KRAS	NSCLC	¹¹³
Heat-shock-protein 90 (HSP90) and MEK	Trametinib and AUY922	Blocking EGFR/PI3K/AKT activation as well as RAF-MEK-ERK pathway, increasing apoptotic signaling and reduction of tumor growth in xenograft experiments	KRAS	NSCLC	³²
MEK1/2 and AKT	Selumetinib (AZD6244; ARRY-142886) and MK-2206	Durable RECIST^* tumor shrinkage in NSCLC and low-grade ovarian carcinoma. No clinical responses for colorectal or small-bowel carcinoma	KRAS	NSCLC, ovarian, colorectal, and small-bowel cancer	³⁴

*Response evaluation criteria in solid tumors