Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.

Abstract

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 such as the EGFR inhibitor (EGFRi), 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 RTKs as the oncogenic driver. In EGFR-mutant 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 EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

• Authors: Yuting Sun, Brooke A Meyers, Barbara Czako, Paul Leonard, Faika Mseeh, Angela L Harris, Qi Wu, Sarah Johnson, Connor A Parker, Jason B Cross, Maria Emilia Di Francesco, Benjamin J Bivona, Christopher A Bristow, Jason P Burke, Caroline C Carrillo, Christopher L Carroll, Qing Chang, Ningping Feng, Guang Gao, Sonal Gera, Virginia Giuliani, Justin K Huang, Yongying Jiang, Zhijun Kang, Jeffrey J Kovacs, Chiu-Yi Liu, Anastasia M Lopez, Xiaoyan Ma, Pijus K Mandal, Timothy McAfoos, Meredith A Miller, Robert A Mullinax, Michael Peoples, Vandhana Ramamoorthy, Sahil Seth, Nakia D Spencer, Erika Suzuki, Christopher C Williams, Simon S Yu, Andy M Zuniga, Giulio F Draetta, Joseph R Marszalek, Timothy P Heffernan, Nancy E Kohl, Philip Jones
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 21 Pg. 4840-4853 (11 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32928921 (Publication Type: Journal Article)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Acrylamides
• Aniline Compounds
• Antineoplastic Agents
• osimertinib
• EGFR protein, human
• ErbB Receptors
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Acrylamides (pharmacology)
• Aniline Compounds (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• ErbB Receptors (genetics)
• Humans
• Lung Neoplasms (genetics, pathology)
• Mice
• Mutation
• Neoplasms, Experimental (genetics, pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors)
• Xenograft Model Antitumor Assays