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Research on the Biologic Mechanism Underlying Acquired Osimertinib Resistance in NSCLC

By: Julia Fiederlein
Posted: Wednesday, October 26, 2022

Douglas K. Graham, MD, PhD, of Emory University School of Medicine, Atlanta, and colleagues identified MERTK as a driver of bypass signaling in treatment-naive, EGFR-mutant, osimertinib-resistant non–small lung cancer (NSCLC) cells. Their findings, which were published in The Journal of Clinical Investigation, suggested patients harboring an EGFR aberration may derive clinical benefit from combination therapy with the MERTK kinase inhibitor MRX-2843 plus osimertinib.

EGFR-mutated tumors treated with combination therapy exhibited durable tumor regression that persisted even after treatment had ended for more than 12 weeks, while half of tumors treated with osimertinib alone regrew,” the investigators remarked. “Based on these findings, we have initiated a phase I trial to determine the safety and therapeutic benefits of this combination in patients.”

The investigators conducted xenograft experiments using mice, cell culture, and several assays to identify the mechanism underlying acquired osimertinib resistance. The MERTK ligand GAS6 seemed to promote downstream oncogenic signaling in EGFR-mutated NSCLC cells treated with osimertinib, suggesting a role for MERTK activation in osimertinib resistance, according to the investigators. Treatment with MRX-2843 appeared to resensitize GAS6-treated NSCLC cells to osimertinib. Although both GAS6 and EGF seemed to stimulate downstream PI3K/AKT and MAPK/ERK signaling in parental cells, GAS6 alone was found to activate these pathways in osimertinib-resistant derivative cell lines.

Osimertinib-resistant cells demonstrated higher sensitivity to MRX-2843 than parental cells; this finding suggests acquired dependence on MERTK signaling. The investigators noted that MERTK and/or its ligands were “dramatically” upregulated in the EGFR-mutated tumors of both xenograft models and patient samples after treatment with osimertinib, which is consistent with the induction of autocrine/paracrine MERTK activation. Treatment with MRX-2843 plus osimertinib was found to suppress tumor growth in vivo, even after treatment was stopped; however, this did not seem to hold true with osimertinib alone.

Disclosure: For full disclosures of the study authors, visit jci.org.


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