From the University of Texas MD Anderson Cancer Center and BridgeBio Pharma, Inc.A new preclinical study by affiliate Navire Pharma, Inc. has found that the novel SHP2 inhibitor iACS-13909 can overcome multiple therapeutic resistance mechanisms (NSCLC) in non-small cell lung cancer, suggesting a potential new approach for treating cancers that have become resistant to the targeted EGFR inhibitor oxitinib.

The data were published today in Cancer Research, a journal of the American Association for Cancer Research.Iacs-13909 is an effective and selective allosteric SHP2 inhibitor developed by Navire and MD Anderson's Therapeutics Discovery division.Based on these data, Navire plans to conduct clinical studies of SHP2 inhibitors by the end of 2020 at several LOCATIONS in the United States, including MD Anderson.

Iacs-13909 was first discovered by a team of scientists in the MD Anderson Institute for Applied Cancer Sciences (IACS) and the TRACTION platform for Translational Research for Tumor Therapy and Innovation.

"Tyrosine kinase inhibitors (such as oxitinib) initially appear to be effective in inhibiting tumor growth, but multiple mechanisms of resistance occur when patients are still on treatment," said Nancy Kohl, Ph.D., senior author of the study.This study shows that iACS-13909's ability to inhibit downstream proteins in multiple signaling pathways is a promising way to overcome these common tumor resistance mechanisms."

Osimertinib is a targeted EGFR inhibitor used as a first-line option in the treatment of NSCLC patients with specific EGFR mutations.However, NSLC often develops oxitinib resistance over time, either by blocking EGFR mutations in drug activity or by activating compensatory signaling pathways.SHP2 is a protein that plays a role downstream of these pathways and is necessary for full activation of the MAPK signaling pathway, which is known to promote tumor growth, proliferation and survival.

Lead author Dr Yuting Sun said: "Our findings suggest that iACS-13909 inhibits tumor cell proliferation in vitro and causes tumor regression in vivo for lung cancer with multiple activated kinases as oncogenic drivers.These data suggest that targeting SHP2 could provide a viable strategy for overcoming oxitinib resistance that occurs through multiple mechanisms."

These results were consistent when IACS-13909 was used as a single drug in combination with osimertinib in vivo.Combination therapy in vitro resulted in a prolonged, more durable response in tumors sensitive to oxitinib and stimulated tumor regression in oxitinib-resistant models.