Abstract 1943: SHP2 inhibition as the backbone of targeted therapy combinations for the treatment of cancers driven by oncogenic mutations in the RAS pathway
Authors: Smith Jacqueline A. , Singh Mallika , Nichols Robert J. , Koltun Elena S. , Yang Yu C. , Wildes David P. , Stahlhut Carlos , Lee Dong , Schulze Chris J. , Reyes Denise , Marquez Abby , Lee Grace J. , Li Shaoling , Marcireau Christophe , Debussche Laurent , Goldsmith Mark A. , Wang Zhengping , Gill Adrian L. , Kelsey Steve M. 
Published: September 2020

Abstract
Direct targeting of oncogenic mutations in the RAS pathway, such as mutant EGFR, BRAFV600E, and most recently KRASG12C, has emerged as a beneficial therapeutic strategy for patients with cancers bearing these mutations. Mutant-selective inhibitors offer the advantage of a wide therapeutic window but are ultimately limited by the emergence of drug resistance. While a variety of resistance mechanisms have been described, escape from mutant-selective inhibitors frequently involves activation of wild type signaling nodes, including hyperactivation of receptor tyrosine kinases (RTKs), that lead to robust re-activation of the RAS pathway. SHP2 (PTPN11) is a phosphatase that functions as a convergent node downstream of multiple RTKs to regulate RAS activation. In the context of adaptive resistance to mutant-selective inhibitors, SHP2 inhibition has the potential to suppress oncoprotein-mediated signaling as well as adaptive signaling driving escape from therapy. Here we show, using in vitro and in vivo systems, that SHP2 inhibitors have the potential to become the backbone of targeted therapy combinations for RAS-dependent tumors. RMC-4630, a potent, selective, orally bioavailable allosteric inhibitor of SHP2, enhanced the anti-tumor activity of mutant-selective inhibitors, as exemplified by preclinical combination studies with EGFR mutant or KRASG12C inhibitors. RMC-4630 accelerated the time to, and increased the magnitude of, tumor regressions in osimertinib-sensitive EGFR-mutant tumors and delayed and/or reduced tumor regrowth in mice upon cessation of treatment. RMC-4630 was also effective at inhibiting tumor growth in a PDX model that had become resistant to osimertinib via amplification of c-MET. Lastly, SHP2 inhibition blocked EGFRL858R/T790M/C797S signaling in vitro indicative of activity against on-target osimertinib resistance mechanisms. Combination benefits were also observed preclinically with KRASG12C mutant-selective inhibitors, such as AMG-510. For other oncogenic drivers in the RAS pathway, including KRASG12D and KRASG12V, NF1LOF, KRAS amplifications or BRAFClass3, mutant-selective inhibitors are not currently available. In these contexts, a combination strategy simultaneously targeting nodes both up- and down-stream of the oncoprotein, a strategy we refer to as “oncoprotein clamping,” was able to drive regressions of tumors. In xenograft models bearing these mutations, RMC-4630 or cobimetinib alone dosed sub-MTD inhibited growth but induced few tumor regressions in mice. However, the corresponding combinations markedly increased the number and depth of tumor regressions. Translation of these preclinical findings into clinical benefit could position RMC-4630, an investigational therapeutic agent, as a backbone of targeted therapy combinations for patients bearing cancers with diverse oncogenic mutations in the RAS pathway.
Citation Format: Jacqueline A. Smith, Mallika Singh, Robert J. Nichols, Elena S. Koltun, Yu C. Yang, David P. Wildes, Carlos Stahlhut, Dong Lee, Chris J. Schulze, Denise Reyes, Abby Marquez, Grace J. Lee, Shaoling Li, Christophe Marcireau, Laurent Debussche, Mark A. Goldsmith, Zhengping Wang, Adrian L. Gill, Steve M. Kelsey. SHP2 inhibition as the backbone of targeted therapy combinations for the treatment of cancers driven by oncogenic mutations in the RAS pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1943.