Hyperactivation of Torc1 Drives Resistance to the Pan-Her Tyrosine Kinase Inhibitor Neratinib in Her2-Mutant Cancers

Abstract

The HER2 tyrosine kinase inhibitor (TKI) neratinib is clinically active in patients with HER2-mutant cancers. However, responses are heterogeneous across tumor types and generally short lived, suggesting mechanisms of de novo and acquired resistance. We developed neratinib-resistant HER2-mutant 5637 bladder and OVCAR8 ovarian cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Treatment with the TORC1 inhibitor everolimus or genetic inactivation of RAPTOR or RHEB ablated p-S6 levels and restored sensitivity to the TKI. The combination of everolimus and neratinib potently arrested growth of neratinib-resistant xenografts. RNA-seq and RAS activity assays revealed significant enrichment of the RAS pathway in neratinib-resistant cells. siRNA mediated knockdown of RAS isoforms also abrogated p-S6 and neratinib resistance. Finally, DNA sequencing of HER2-mutant tumors from patients clinically refractory to neratinib showed enrichment of somatic alterations associated with aberrant activation of the mTOR pathway.