Abstract 2669: ERAS-007 (ERK inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models

Abstract

Abstract KRAS mutations occur in about 25% of all cancers and promote oncogenesis via constitutive activation of the RAS/MAPK pathway. Targeting KRAS mutant tumors by inhibiting individual nodes in the RAS/MAPK pathway, including SHP2, SOS1, KRAS, RAF, MEK, and ERK, has shown early clinical activity, but the rapid emergence of resistance limits the benefit of monotherapy. Resistance is often mediated by reactivation of RAS/MAPK pathway signaling, which can occur by increased activation of upstream of the RAS/MAPK pathway (e.g., EGFR activation) and/or activation of RAS/MAPK pathway nodes (e.g., oncogenic BRAF and MEK mutations). Inhibiting both upstream and downstream RAS/MAPK pathway nodes has the potential to more robustly prevent reactivation relative to inhibition of a single node alone. We are currently exploring the combination of an inhibitor of an upstream node, SHP2, with ERAS-601 and the terminal downstream node, ERK1/2, with ERAS-007 (our first “MAPKlamp”) in nonclinical models. We evaluated this MAPKlamp in NSCLC, CRC, and pancreatic tumor models that harbored KRAS mutations in vitro and in vivo. In 14-day clonogenic assays in KRAS mutant NSCLC, CRC, and PDAC cell lines, this MAPKlamp inhibited colony growth more potently than ERAS-601 or ERAS-007 alone. In KRAS mutant CDX and PDX models, this MAPKlamp’s in vitro activity was observed in vivo where it achieved superior tumor growth inhibition and tumor regression relative to ERAS-601 and ERAS-007 monotherapy. This MAPKlamp showed in vitro and in vivo combination activity in KRAS mutant tumors, and these results support its clinical evaluation in RAS/MAPK pathway-driven tumors. Citation Format: Leenus Martin, Erin D. Lew, Roopal Patel, Joanne Oh, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Wei Lin, Les Brail, Robert Shoemaker. ERAS-007 (ERK inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2669.