Abstract 1322: Maximizing the therapeutic potential of SHP2 inhibition with rational combination strategies in tumors driven by aberrant RAS-MAPK signaling

Abstract

Abstract SHP2 (PTPN11) is a protein tyrosine phosphatase and scaffold protein that functions as a convergent node downstream of multiple receptor tyrosine kinases (RTKs), integrating growth factor signals to promote RAS activation. Recently we reported that a SHP2 allosteric inhibitor suppresses RAS activation and proliferation in cancers driven by nucleotide cycling oncogenic KRAS, e.g., KRASG12C and other RAS-GTP dependent downstream mutations, e.g., NF1LOF, BRAFclass3. Daily oral administration of a SHP2 allosteric inhibitor at the maximally tolerated dose achieved tumor cytostasis in cell line-derived and patient-derived xenograft models harboring these mutations, and in some instances, tumor regressions. In most models, tumor cytostasis was followed by regrowth of tumors, reminiscent of patterns observed with MEK inhibitors. In the NCI-H358 KRASG12C model of non-small cell lung cancer, the maximum daily dose of the SHP2 inhibitor resulted in ~75% inhibition (relative to control) of pERK1/2, a downstream indicator of RAS-MAPK signaling in tumor lysates. These results support the hypothesis that targeting a single node results in incomplete RAS-MAPK pathway inhibition, which may permit tumor persistence in these models. To achieve deeper suppression of oncogenic flux through the RAS-MAPK pathway in tumors driven by nucleotide cycling KRAS, NF1LOF, or BRAFclass3, we evaluated combinations of MEK and ERK inhibitors with a SHP2 inhibitor as rational “in-pathway”, anti-proliferative combinations. Additionally, we examined the combination with CDK4/6 inhibition as a strategy to impact RAS-MAPK signaling both directly and via cell cycle effects. We found that concurrent targeting of SHP2 and MEK or ERK drives greater anti-tumor efficacy than that observed with monotherapy with either agent. Comparable synergy was observed when SHP2 inhibition was combined with CDK4/6 inhibition. Given the complementary anti-tumor mechanisms triggered by MEK/ERK and CDK4/6 inhibition, we further interrogated a triple combination of SHP2, MEK, and CDK4/6 inhibition to drive complete elimination of RAS-MAPK oncogenic signals. We found that this combination regimen was tolerated, resulted in more significant responses in all tumor models we tested, and delayed the evolution of on-treatment resistance. Investigation of the downstream effects of the triple therapy on tumor cells revealed profound combinatorial effects on cell cycle progression, proliferation and induction of apoptosis. These observed synergies are likely due to a combination of RAS pathway extinction and the inhibition of parallel escape mechanisms. In summary, our findings reveal rational combination strategies to maximize the therapeutic potential of a potent SHP2 inhibitor in patients with tumors harboring nucleotide cycling oncogenic KRAS or other RAS-GTP-dependent downstream mutations. Citation Format: Grace J. Lee, Carlos Stahlhut, James Evans, Denise F. Reyes, Edward G. Lorenzana, Shaoling Li, Elena S. Koltun, Dong Lee, Zhengping Wang, Robert J. Nichols, Jacqueline A. Smith, Mallika Singh. Maximizing the therapeutic potential of SHP2 inhibition with rational combination strategies in tumors driven by aberrant RAS-MAPK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1322.