The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, functions as a convergent node downstream of multiple receptor tyrosine kinases (RTKs) and is required for full activation of the MAPK pathway. Suppression of SHP2 activity via either genetic silencing or pharmacological inhibition has been shown to inhibit RAS/MAPK signaling and cell growth in a wide spectrum of cancers, pointing to a therapeutic opportunity for targeting SHP2 in cancer therapy. Here we report the discovery of a highly potent, selective and orally bioavailable small-molecule allosteric inhibitor of SHP2, ETS-001, that is effective in various human cancer models bearing oncogenic alterations in the RTK/RAS/MAPK pathway. Treatment with ETS-001 as a single agent resulted in dramatic growth inhibition of cancer cells as well as in vivo tumor models bearing genetic alterations of EGFR, or components in the nucleotide cycling-dependent KRAS pathway. Besides, as the effectiveness of RAS pathway inhibitors are ultimately limited by rapid emergence of drug resistance via multiple mechanisms including bypass activation of alternative RTKs, SHP2 inhibition has the potential to overcome the resistance as combinational strategies associated with various RAS pathway-targeted therapies. Here we show that ETS-001 exhibited strong synergistic effect with EGFR-TKI (osimertinib), KRASG12Ci (AMG510) or CDK4/6i (ribociclib) in appropriate cancer models in vitro and in vivo. In EGFR mutant NSCLC cells, treatment with both ETS-001 and osimertinib showed combinational benefit that was coincident with sustained ERK inhibition. In a KRASG12C mutant pancreatic cancer cell xenograft model, ETS-001 greatly enhanced the efficacy of AMG510 to suppress in vivo tumor growth. In addition, combinational benefit of ETS-001 and ribociclib was observed in esophageal cancer models, which exhibited high frequency of concurrent oncogenic alterations in RTKs and cell cycle pathway. Taken together, our findings provide preclinical evidence that ETS-001 as a potent SHP2 inhibitor, alone or in combination with other targeted-therapy agents, can effectively inhibit MAPK activation and treat cancers with diverse oncogenic mutations in the RAS/MAPK pathway. Citation Format: Xi Xia, Lin Du, Hao Zhuge, Qiangang Zheng, Wenqi Cui, Jidong Zhu, Guo Li. Discovery of ETS-001, a highly potent allosteric SHP2 inhibitor to treat RTK/RAS-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1475.