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Restoring Drug Sensitivity to BRAF and MEK Inhibition in Double-Resistant Melanoma Cells

By: Jenna Carter, PhD
Posted: Friday, May 17, 2024

In a recent presentation at the American Association for Cancer Research (AACR) Annual Meeting 2024 (Abstract 5869/13), researchers highlighted the molecular mechanisms associated with BRAF and MEK inhibitor resistance in patients with melanoma. Glen Merlino, PhD, of the National Institutes of Health, Bethesda, Maryland, and colleagues developed models from four human melanoma cell lines and examined the molecular alterations involved in double resistance. Ultimately, their findings revealed that BRAF inhibitor/MEK inhibitor double-resistant models displayed distinct differences in growth kinetics and morphology, and decreasing expression of specific overexpressed genes may restore drug sensitivity.

“Inhibition of mutant BRAF by BRAF inhibitors in patients with advanced melanoma yields a remarkable initial clinical response. Limited duration response and disease recurrence of inhibitors occurs due to acquired drug resistance. Recently identified mechanisms of MAPK hyperactivation in acquired resistance to BRAF inhibitors have encouraged clinicians to employ a combination of BRAF and MAPK inhibitors…. However, most patients treated with this combination therapy still relapse due to de novo drug resistance,” stated the investigators.

Via assays assessing growth kinetics and morphologic changes, four different human melanoma cell lines were examined, with specific characterization of FGFb (basic fibroblast growth factor) and PAI-1 (plasminogen activator inhibitor-1) expression. Knockdown of FGFb and PAI-1 was then performed along with inhibition and CRISPR to assess whether reductions in these molecular targets would restore drug sensitivity.

Overall findings revealed distinct morphologic differences and growth patterns in the models that were BRAF inhibitor/MEK inhibitor double-resistant. Specific findings highlighted higher levels of FGFb and PAI-1 in double-resistant human melanomas, and overexpression of these genes in parental cells seemed to lead to increased resistance of BRAF and MEK inhibition. Moreover, decreased expression of FGFb and PAI-1, via knockdown, inhibition, or CRISPR in double-resistant cells, seemed to result in restored cell sensitivity to treatments.

Disclosure: The study authors reported no conflicts of interest.


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