Abstract 2670: ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC tumor models

ERAS-601 is a potent, small molecule allosteric inhibitor of wildtype SHP2, a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. ERAS-601 inhibits wild type SHP2 biochemically with an IC50 of 4.6 nM and demonstrates selectivity across panels of 300 kinases and 12 phosphatases. SHP2 mediates upstream receptor tyrosine kinase (RTK) signaling via its phosphatase-mediated regulation of guanine nucleotide exchange factors (GEFs). ERAS-601 inhibits the SHP2 dependent cycling of KRAS from the inactive GDP-bound state to the active GTP-bound state and demonstrates anti-proliferative activity in KRASG12C and EGFR amplified cell lines. The combination of upstream blockade of RAS-GTP cycling by ERAS-601 with inhibition of KRASG12C by a selective KRASG12C inhibitor synergistically inhibits cellular proliferation in multiple KRASG12C mutated human cancer cell lines. The combinations of ERAS-601 with KRASG12C inhibitors achieve tumor growth inhibition that is superior to the respective ERAS-601 and KRASG12C monotherapies in NSCLC and CRC CDX and PDX tumor models. Similarly, the combination of ERAS-601 with an EGFR antibody, cetuximab, inhibits oncogenic RAS/MAPK signaling as measured by pERK1/2 and enhances the anti-proliferative activity of cetuximab in RAS/RAF wild type CRC and HPV-negative HNSCC cell lines. The combination of ERAS-601 with cetuximab achieves tumor growth inhibition that is superior to respective ERAS-601 and cetuximab monotherapies in RAS/RAF wild type CRC and HPV-negative HNSCC CDX and PDX tumor models. These nonclinical data support the clinical development of ERAS-601 in combination with a KRASG12C inhibitor in NSCLC and CRC tumors, and ERAS-601 in combination with cetuximab in RAS/RAF wild type CRC as well as HPV-negative HNSCC tumors. Both combinations are being studied in ongoing clinical studies (HERKULES-2, NCT04959981; FLAGSHP-1, NCT04670679). Citation Format: Leenus Martin, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker. ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC 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 2670.