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Ref Type Journal Article
PMID (32928921)
Authors Sun Y, Meyers BA, Czako B, Leonard P, Mseeh F, Harris AL, Wu Q, Johnson S, Parker CA, Cross JB, Di Francesco ME, Bivona BJ, Bristow CA, Burke JP, Carrillo CC, Carroll CL, Chang Q, Feng N, Gao G, Gera S, Giuliani V, Huang JK, Jiang Y, Kang Z, Kovacs JJ, Liu CY, Lopez AM, Ma X, Mandal PK, McAfoos T, Miller MA, Mullinax RA, Peoples M, Ramamoorthy V, Seth S, Spencer ND, Suzuki E, Williams CC, Yu SS, Zuniga AM, Draetta GF, Marszalek JR, Heffernan TP, Kohl NE, Jones P
Title Allosteric SHP2 inhibitor IACS-13909 overcomes EGFR-dependent and EGFR-independent resistance mechanisms towards osimertinib.
Journal Cancer research
Vol
Issue
Date 2020 Sep 14
URL
Abstract Text Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors (TKI) such as the EGFR inhibitor osimertinib in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2 that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTK as the oncogenic driver. In EGFRmut osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFR inhibitor-resistant NSCLC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
IACS-13909 IACS13909|IACS 13909|BBP-398|IACS-15509 SHP2 Inhibitor 18 IACS-13909 binds to and inhibits the phosphatase activity of Shp2, inhibits signaling through the MAPK pathway, potentially inhibiting cell proliferation and tumor growth (PMID: 32928921).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive IACS-13909 Preclinical - Cell line xenograft Actionable In a preclinical study, IACS-13909 decreased Erk phosphorylation and inhibited proliferation in a acute myeloid leukemia cell line harboring a FLT3-ITD in culture, and inhibited tumor growth and increased overall survival in cell line xenograft models (PMID: 32928921). 32928921