LAUSR

Adaptive resistance remains a major challenge limiting the clinical effectiveness of inhibitors of oncogenic MAPK signaling (RAF and MEK inhibitors), there is thus a pressing need for compounds and combinatorial strategies that would potently and durably suppress MAPK signaling in the tumor, while retaining a broad therapeutic window. A common mechanism of adaptive resistance is mediated by feedback-induced RTKs and RAS activation by inhibitor that results in incomplete MAPK inhibition in the tumor. SHP2 (PTPN11) is a non-receptor tyrosine phosphatase and scaffold protein that mediates signal transduction downstream of multiple RTKs promoting RAS activation. Targeting SHP2 provides the opportunity to overcome adaptive resistance by co-targeting MAPK signaling and feedback-induced RTK-mediated RAS activation. Targeting SHP2 using a selective allosteric SHP2 inhibitor, in combination with inhibitors of components of MAPK signaling, prevents adaptive resistance and is broadly effective in Triple Negative Breast Cancer models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. This indicates that different RAS mutant proteins vary considerably in the dependence of their activity on upstream RTK/SHP2 signaling, suggesting hitherto unappreciated differences in their biochemical properties in cells. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to MAPK signaling inhibition. In addition, a subset of BRAF(V600E) tumors was identified that were resistant to the combined treatment. In such tumors, FGFR signaling was found to drive feedback-induced RAS activation independently of SHP2, indicating additional combinatorial pharmacologic approaches for this subset of tumors. Thus, understanding mechanisms of adaptive resistance and response to pharmacologic perturbations of oncogenic signaling enables the rational design of more effective combinatorial strategies for the treatment of MAPK-driven cancers. Citation Format: Poulikos Poulikakos. Next generation strategies to overcome adaptive resistance to MAPK-directed therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN05-02. doi:10.1158/1535-7163.TARG-19-CN05-02