Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells

Abstract

Background As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. Methods The combined antitumor effects of HS‐10296, a third‐generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non‐small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies. Results Famitinib strengthened the effects of HS‐10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS‐10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS‐10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS‐10296 and famitinib exerted synergistic antitumor activity in NCI‐H1975 and PC‐9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues. Conclusions Collectively, our results indicate that HS‐10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third‐generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR‐mutant NSCLC.

The effect of Rifampin on the Pharmacokinetics of Famitinib in Healthy Subjects

“…Single doses of famitinib 25mg were well tolerated in healthy subjects when given alone and in combination with multiple doses of rifampin. The major adverse reactions (incidence rate >30%) after continuous administration of famitinib in cancer patients were hypertension, hand-food skin reaction, oral mucositis, bone marrow suppression, diarrhea, proteinuria, hypertriglyceridemia, fatigue, liver dysfunction, etc [3,5,6,8]. In this study, the famitinib-related adverse events were in line with the known safety profile.…”

“…famitinib, SHR1020), is an orally active, small-molecule, multi-targeted and potent TKI that inhabits various TKRs including c-Kit, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), FMS-like tyrosine kinase-3 receptor (FLT3), KDR and RET. Famitinib not only inhabits the angiogenesis, but also directly inhabits the expansion of tumor cells, which have been verified both in vivo and in vitro [2,3]. Completed Phase I and II studies in patients with advanced solid cancer have demonstrated that famitinib is well tolerated and has a broad spectrum of antitumor activities [4][5][6][7][8].…”

The effect of rifampin on the pharmacokinetics of famitinib in healthy subjects

“…famitinib, SHR1020) is an orally active, small-molecule, multi-targeted and potent TKI that inhibits various TKRs including c-Kit, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), FMS-like tyrosine kinase-3 receptor (FLT3) and RE arranged during Transfection (RET). Famitinib not only inhibits the angiogenesis, but also directly inhibits the expansion of tumor cells, which have been verified both in vivo and in vitro [ 2 , 3 ]. Completed Phase I and II studies in patients with advanced solid cancer have demonstrated that famitinib is well tolerated and has a broad spectrum of antitumor activities [ 4 – 8 ].…”

Evaluation of gastric pH-dependent drug interaction between famitinib and the commonly used proton pump inhibitor omeprazole in healthy subjects

“…Famitinib is a structural analog of sunitinib with improved cell inhibitory activity. Due to its anti-angiogenic effect, it was effective against metastatic renal cell carcinoma, non-small cell lung cancer and metastatic breast cancer [11][12][13] . Clinical trials of famitinib in combination with the concurrent medication or chemoradiotherapy also showed its good antitumor abilities against other solid tumors such as metastatic urothelial carcinoma, advanced immunomodulatory triple-negative breast cancer, advanced nasopharyngeal carcinoma, platinum-resistant recurrent ovarian cancer, advanced colorectal cancer and gastric cancer 9,[14][15][16][17][18][19][20] .…”