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Alexander Drilon, MD

Gregory J. Riely, MD, PhD


Brain Metastasis Model of NTRK-Rearranged Tumors: Focus on Treatment Resistance

By: Kayci Reyer
Posted: Tuesday, June 28, 2022

According to research presented in Cancer Science, resistance to second-generation TRK inhibitors such as repotrectinib may be triggered by resistant mutations plus alternative pathway activation in patients with NTRK gene fusion. The simultaneous occurrence of NTRK-GF95R and extracellular signal–regulated kinase activation within a tumor that is less vulnerable to the first-generation inhibitor entrectinib, for example, may prompt second-generation treatment resistance as well.

“These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance,” concluded Seiji Yano, MD, PhD, of Kanazawa University, Japan, and colleagues.

The study used a brain metastasis model that included M3B tumor cells that were resistant to entrectinib. NTRK1-rearranged KM12SM cells were inserted into the model before the repotrectinib sensitivity of the M3B cells was evaluated. Contrary to expectations, M3B cells that contained an NTRK1-G595R mutation were resistant to repotrectinib. The resistance appeared to be a ripple effect of EGFR activation, which impacted extracellular signal–regulated kinase reactivation and prompted resistance. To combat resistance, a three-pronged treatment approach of repotrectinib, an EGFR inhibitor, and a mitogen-activated extracellular signal–regulated kinase inhibitor was found to increase the sensitivity of M3B cells to second-generation repotrectinib.

The study authors acknowledged the limitations of this study; only M3B cells were analyzed as TRK inhibitor–resistant NTRK1-rearranged tumor cells. “As NTRK-rearranged cancer is a rare disease, we were unable to obtain other native tumor cell lines with NTRK1 rearrangement,” they noted. “Further experiments with other NTRK1-rearranged tumor cells and clinical specimens are warranted in future to delineate the clinical relevance of our results obtained in the present study.”

Disclosure: For full disclosures of the study authors, visit

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