EGFR is a validated therapeutic target in many human cancers. EGFR targeted therapies are in widespread clinical use in patients with non-small cell lung cancer and other tumor types. Despite the clinical success of EGFR targeted therapy, resistance to treatment is a significant barrier to the optimized use of EGFR inhibitors to cure patients with lung and other cancers. Here, we review established and emerging mechanisms of resistance to EGFR targeted therapy and highlight strategies that could overcome treatment resistance and therefore enhance clinical outcomes.

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Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of “bi-steric inhibitors” that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRAS G12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.

KRASG12V mutant cancers represent a significant unmet medical need with nearly 44,000 new diagnoses annually in the US. The KRASG12V mutation occurs frequently in multiple tumor histotypes; the incidence in NSCLC, CRC and pancreatic cancers is 6%, 10% and 26%, respectively. RAS proteins are small GTPases that drive cell proliferation and survival when bound to GTP. Mutant RAS proteins exist predominantly in the GTP-bound (RAS(ON)) state, leading to excessive downstream signaling via interaction with effectors such as RAF. The intrinsic GTP hydrolysis rate of KRASG12V is significantly lower than that of either KRASG12C or KRASG12D. Therefore, targeting the KRASG12V(ON) state will be critical for maximal suppression of this oncogenic driver. No targeted, direct inhibitors of KRASG12V(ON) have been described to date. We have built a pipeline of small molecule inhibitors targeting multiple oncogenic RAS(ON) mutants. Here we describe the preclinical profile of KRASG12V(ON) inhibitors that promote a tri-complex between the inhibitor, the immunophilin cyclophilin A (CypA), and the active GTP-bound state of KRASG12V. In cancer cell lines bearing KRASG12V mutations, KRASG12V(ON) inhibitors trigger an immediate disruption of RAS-effector interactions, leading to attenuation of RAS pathway signaling, potent (sub-nM EC50) growth suppression, and apoptosis. KRASG12V(ON) inhibitors produce deep, durable, and dose-dependent suppression of tumor RAS pathway activation in vivo following oral administration. An extended duration of tumor pharmacodynamic activity, relative to plasma exposure, is observed that likely reflects retention of the inhibitors in tumor tissue due to high affinity binding to CypA. In human tumor xenograft models of KRASG12V mutant NSCLC, CRC and pancreatic cancers, oral administration of KRASG12V(ON) inhibitors is well-tolerated and drives profound and durable tumor regressions, with complete responses in some animals. KRASG12V(ON) inhibitors also downregulate immune checkpoint proteins PD-L1 and CD73 on KRASG12V mutant cancer cells, changes which can support enhanced anti-tumor immunity. The ability to target the GTP-bound form of mutant KRASG12V permits a broad array of combination opportunities in cancer types where single agent KRASG12V(ON) inhibition may be insufficient, for example with agents targeting pathway nodes both upstream (e.g. SHP2, SOS1) and downstream (e.g. MEK, ERK) of RAS, as well as parallel pathways (e.g. mTORC1). Tri-complex inhibitors that target KRASG12V(ON) are predicted to combat escape mechanisms in RAS-addicted cancer cells characterized by an increased pool of activated KRASG12V(ON). These inhibitors may lead to an attractive, targeted therapeutic option for the treatment of RAS-addicted cancers with a very high unmet medical need. Citation Format: Elena Koltun, Jim Cregg, Meghan A. Rice, Dan M. Whalen, Rebecca Freilich, Jingjing Jiang, Richard Hansen, Alun Bermingham, John E. Knox, Jay Dinglasan, Kyle Seamon, Cristina Blaj, Stephanie S. Chang, Yang Liu, Jun Huang, Kang-Jye Chou, Laura McDowell, Bianca J. Lee, David Wildes, Zhengping Wang, Mallika Singh, Adrian L. Gill, Jacqueline A. Smith. First-in-class, orally bioavailable KRASG12V(ON) tri-complex inhibitors, as single agents and in combinations, drive profound anti-tumor activity in preclinical models of KRASG12V mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1260.