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SHP2 Inhibition May Counter Resistance Mechanisms in Lung Cancer


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Recent preclinical research from The University of Texas MD Anderson Cancer Center and BridgeBio Pharma, an affiliate of Navire Pharma, found that the novel SHP2 inhibitor IACS-13909 may be able to overcome therapeutic resistance mechanisms in non–small cell lung cancer (NSCLC). The data, which appeared in Cancer Research, suggest a possible new approach to treating cancers that have developed resistance to the targeted EGFR inhibitor osimertinib.1

IACS-13909 is a selective allosteric SHP2 inhibitor developed through collaboration between Navire Pharma and MD Anderson’s Therapeutics Discovery division.

How It Works

Nancy Kohl, PhD

Nancy Kohl, PhD

“Tyrosine kinase inhibitors, like osimertinib, appear initially effective in suppressing tumor growth, but multiple mechanisms of resistance can develop while a patient is still receiving treatment,” said Nancy Kohl, PhD, a senior author of the study and a member of Navire Pharma’s scientific advisory board. “This study shows that IACS-13909’s ability to inhibit a protein downstream of multiple signaling pathways is a promising approach in overcoming these common tumor resistance mechanisms.”

Patients with NSCLC frequently develop osimertinib resistance over time, either through additional mutations in EGFR that block activity of the drug or by activating compensatory signaling pathways. SHP2 is a protein that acts downstream in these pathways, and it is required for full activation of the MAPK signaling pathways, which is known to fuel tumor growth, proliferation, and survival.

The study results were consistent when IACS-13909 was used as a single agent and in combination with osimertinib in vivo. The combination treatment in vitro led to prolonged, more durable responses in tumors that were sensitive to osimertinib and stimulated tumor regression in osimertinib-resistant models. 

DISCLOSURE: The ongoing research is supported by Navire Pharma through a global licensing and development agreement, and the Therapeutics Discovery division is supported in part by MD Anderson’s Moon Shots Program. MD Anderson has received institutional funding from Navire Pharma, and the research is managed according to MD Anderson’s Institutional Conflict of Interest Management and Monitoring Plan. For full disclosures of all study coauthors, visit aacrjournals.org.

REFERENCE

1. Sun Y, Meyers, BA, Czako B, et al: Allosteric SHP2 inhibitor IACS-13909 overcomes EGFR-dependent and EGFR-independent resistance mechanisms towards osimertinib. Cancer Res. September 14, 2020 (early release online).

 


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