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MAPK Signaling and CIC-Mediated Modulation in NTRK Fusion Sarcomas

By: Vanessa A. Carter, BS
Posted: Monday, February 28, 2022

Romel Somwar, PhD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues generated models of sarcomas bearing NTRK fusions and evaluated their response to molecularly targeted therapy. Published in Cancer Research, this work introduces new tools and insights to improve personalized therapy approaches for these kinase-addicted sarcomas and supports the use of combination therapy to encourage prolonged responses. 

“Capicua [CIC]-mediated suppression of negative MAPK pathway regulators was identified as a potential mechanism by which these sarcomas compensate for [NTRK inhibition],” concluded the study authors.

The ETV6-NTRK3 rearrangement is among the most common NTRK fusions that are oncogenic drivers in some sarcomas, such as infantile fibrosarcoma. A patient-derived ETV6-NTRK3–rearranged infantile fibrosarcoma model was employed to assess whether feedback inhibition of the MAPK pathway dampens the therapeutic efficacy of NTRK kinase inhibitors. Consistent with previous findings using RET models, the sarcoma cells appeared to overexpress multiple negative regulators of this MAPK pathway.

NTRK inhibitors were then selected to determine the sensitivity of sarcoma cells to therapy. Treatment with repotrectinib resulted in NTRK3 inhibition, and cells treated with trametinib, ulixertinib, and repotrectinib appeared to induce rapid suppression of DUSP4 and DUSP6. To determine whether NTRK3 inhibition or the MAPK pathway impacts nuclear traffic of capicua, cytoplasmic and nuclear fractions were isolated after repotrectinib and trametinib treatment. These results suggest that inhibition of P90RSK phosphorylation may be responsible for nuclear capicua accumulation delay.

To further this study, repotrectinib was then combined with the ERK inhibitor SCH772984, the ERK inhibitor ulixertinib, or the MEK inhibitor trametinib to evaluate how these agents impact cell growth. Of note, these drug combinations appeared to demonstrate significant synergy with 17 combinations in SCH772984, 15 in ulixertinib, and 14 in trametinib. Notably, following NTRK inhibition, capicua accumulates in the nucleus simultaneously with a loss of expression of multiple negative regulators of the MAPK pathway.

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


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