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

Media type: E-Article

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

Contributor: 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; [...]

imprint: American Association for Cancer Research (AACR), 2019

Language: English

DOI: 10.1158/1535-7163.targ-19-c036

ISSN: 1535-7163; 1538-8514

Keywords: Cancer Research ; Oncology

Origination:

Footnote:

Description: Abstract 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

Access State: Open Access

Search in field:

Recently searched for: