Abstract LB-119: SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors

Deregulated RTK/RAS/RAF/MEK/ERK signaling (MAPK signaling) drives growth of over 40% of human tumors, most commonly due to activating mutations of pathway components such as in RAS and BRAF genes. Targeting MAPK signaling using RAF and MEK inhibitors elicited remarkable responses and prolonged survival of melanoma patients with BRAF(V600E) mutation, it however showed limited efficacy in colorectal and thyroid BRAF(V600E) cancers. Similarly, MEK inhibitors showed modest effect in other MAPK-dependent tumors, such as RAS-mutant tumors or in Triple-Negative Breast Cancers (TNBC). We and others have shown that relief of negative-feedback upon RAF or MEK inhibitor treatment promotes upregulation of various Receptor Tyrosine Kinases (RTKs), which in turn activate RAS, resulting in rebound of ERK activity in the presence of the inhibitor. Individual targeting of RTKs in combination with RAF or MEK inhibitors is challenging, due to variability in RTK expression in the same tumor as well as across different tumors. SHP2 (PTPN11) is a non-receptor tyrosine phosphatase and scaffold protein that mediates signal transduction downstream of multiple RTKs promoting RAS activation. The recent development of selective small-molecule SHP2 inhibitors provides the opportunity to overcome adaptive resistance by co-targeting MAPK signaling and feedback-induced RTK-mediated RAS activation. By using the allosteric SHP2 inhibitor SHP099, we found that combinatorial targeting of SHP2 and components of MAPK signaling was broadly effective in TNBC models and molecularly defined subsets of RAS and BRAF-mutant tumors. Notably, in each MAPK-driven tumor analyzed, p(Y542)SHP2 induction in response to MAPK signaling inhibition was required for combined treatment sensitivity. In RAS-mutant tumors, sensitivity to combined SHP2 and MEK inhibition was confined to RAS(G12X) tumors, in which mutant RAS depends on RTK-mediated nucleotide exchange for its activity. In tumors expressing RAS(G13D) or RAS(Q61X) the combination was largely ineffective. We further identified BRAF(V600E) colorectal and thyroid tumors in which feedback reactivation of ERK is driven by ERBB or MET receptors and is therefore mediated by SHP2 ("SHP2-positive" tumors). In such tumors, mostly colorectal, the combination of RAF and MEK inhibitors with SHP099 showed dramatic inhibition of MAPK signaling and tumor growth, both ex vivo and in vivo. Finally, we identified a subset of BRAF(V600E) tumors, mostly thyroid, that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Collectively, our findings identify molecular determinants and predictive biomarkers of response to combined SHP2/MAPK signaling inhibition, providing a roadmap for the clinical development of this combinatorial treatment strategy for MAPK-dependent tumors, such as TNBC, and large subsets of RAS-mutant and BRAF-mutant tumors, for which there are no currently available targeted therapeutic options. Citation Format: Christos Adamopoulos, Tamer A. Ahmed, Zoi Karoulia, Xuewei Wu, Ravi Sachidanandam, Stuart A. Aaronson, Poulikos I. Poulikakos. SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors [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 LB-119.