Abstract C036: Discovery of IACS-13909, an allosteric SHP2 inhibitor that overcomes multiple mechanisms underlying osimertinib resistance

• Published in: Molecular cancer therapeutics Vol. 18; no. 12_Supplement; p. C036
• Main Authors: Sun, Yuting, Meyers, Brooke A, Johnson, Sarah B, Harris, Angela L, Czako, Barbara, Cross, Jason B, Leonard, Paul G, Mseeh, Faika, Francesco, Maria E Di, Parker, Connor A, Wu, Qi, Bristow, Christopher A, Burke, Jason P, Carrillo, Caroline C, Carroll, Christopher L, Chang, Qing, Feng, Ningping, Gera, Sonal, Guang, Gao, Huang, Justin Kwang-Lay, Jiang, Yongying, Kang, Zhijun, Kovacs, Jeffrey J, Ma, Xiaoyan, Mandal, Pijus K, McAfoos, Timothy, Mullinax, Robert A, Peoples, Michael D, Ramamoorthy, Vandhana, Seth, Sahil, Suzuki, Erika, Williams, Christopher Conrad, Yu, Simon S, Zuniga, Andy M, Draetta, Giulio F, Marszalek, Joseph R, Heffernan, Timothy P, Kohl, Nancy E, Jones, Philip
• Format: Journal Article
• Language: English
• Published: 01-12-2019
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-19-C036

Osimertinib, a third generation EGFR inhibitor, is a front-line therapy for EGFR mutated non-small lung cancer (NSCLC). The long-term effectiveness of osimertinib is limited by acquired resistance. Clinically identified resistance mechanisms include EGFR-dependent mechanisms such as mutations on EGFR that preclude drug binding, and EGFR-independent activation of the MAPK pathway, for instance via activation of alternate RTKs. It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between the multiple resistance mechanisms will restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. SHP2 (Src homology 2 domain-containing phosphatase) is a phosphatase that mediates the signaling of multiple RTKs and is required for full activation of the MAPK pathway. Here we report IACS-13909 - a specific and potent allosteric inhibitor of SHP2 - suppresses the signaling of RTK/MAPK pathway. IACS-13909 potently impedes the proliferation of tumors with a broad spectrum of RTKs as the oncogenic driver. Importantly, in NSCLC models with acquired resistance to osimertinib, IACS-13909 administered as a single agent or in combination with osimertinib potently reduces tumor cell proliferation in vitro and in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFR inhibitor-resistant NSCLC. Currently, a compound that potently inhibits SHP2 has been selected as the clinical development candidate and is undergoing IND-enabling studies with a projected first-in-human target of early 2020.
Citation Format: Yuting Sun, Brooke A Meyers, Sarah B Johnson, Angela L Harris, Barbara Czako, Jason B Cross, Paul G Leonard, Faika Mseeh, Maria E Di Francesco, Connor A Parker, Qi Wu, Christopher A Bristow, Jason P Burke, Caroline C Carrillo, Christopher L Carroll, Qing Chang, Ningping Feng, Sonal Gera, Gao Guang, Justin Kwang-Lay Huang, Yongying Jiang, Zhijun Kang, Jeffrey J Kovacs, Xiaoyan Ma, Pijus K Mandal, Timothy McAfoos, Robert A Mullinax, Michael D Peoples, Vandhana Ramamoorthy, Sahil Seth, Erika Suzuki, Christopher Conrad Williams, Simon S Yu, Andy M Zuniga, Giulio F Draetta, Joseph R Marszalek, Timothy P Heffernan, Nancy E Kohl, Philip Jones. Discovery of IACS-13909, an allosteric SHP2 inhibitor that overcomes multiple mechanisms underlying osimertinib resistance [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 C036. doi:10.1158/1535-7163.TARG-19-C036