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Can AXL Inhibitor Overcome Treatment Resistance in EGFR-Mutant Lung Cancer?

By: Cordi Craig
Posted: Monday, June 15, 2020

Anexelekto (AXL) is a tyrosine kinase receptor associated with poor prognosis in several different cancers. The activation of this receptor may result in “drug-tolerant” cells being able to maintain cell viability in EGFR-mutant non–small cell lung cancer (NSCLC). However, Koichi Takayama, PhD, of the Kyoto Prefectural University of Medicine, Japan, and colleagues suggest that ONO-7475, a novel AXL inhibitor, may suppress the emergence and maintenance of tolerant cells to initial EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that overexpress anexelekto. According to the results, published in Clinical Cancer Research, ONO-7475 and osimertinib may prove to be an effective initial treatment combination for these patients.

Using in vitro and in vivo experiments, the researchers tested the efficacy of ONO-7475 in combination with EGFR TKIs in NSCLC cells. The relationship between clinical outcomes with osimertinib and AXL expression in tumors was analyzed in patients with EGFR-mutated NSCLC who had acquired resistance to initial EGFR TKIs.

ONO-7475 sensitized EGFR-mutant cells that were overexpressing AXL to the TKIs osimertinib and dacomitinib. ONO-7475 also suppressed the emergence and preservation of EGFR-TKI–tolerant cells. In xenograft models, when EGFR-mutated lung cancer with AXL overexpression was treated with osimertinib, the combination with ONO-7475 regressed tumors and delayed tumor growth substantially more than osimertinib alone or after acquired resistance to osimertinib. In EGFR-TKI–refractory tumors, AXL expression was not associated with osimertinib sensitivity.

“Further clinical investigations are warranted for the development of novel strategies using an anexelekto inhibitor at the initial therapeutic setting to overcome the tolerance to the EGFR-TKIs osimertinib and dacomitinib in AXL-overexpressing EGFR-mutated NSCLC patients,” the investigators stated.

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



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