Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal.

Background: Although BRAF/MEK inhibitors improved the treatment of melanoma patients, resistance is acquired almost inevitably.

Methods: Trametinib withdrawal/rechallenge and MCL-1 inhibition in trametinib-resistance models displaying distinct p-ERK1/2 levels were investigated.

Results: Trametinib withdrawal/rechallenge caused reversible changes in ERK1/2 activity impacting the balance between pro-survival and pro-apoptotic proteins.

Trametinib-Resistant Melanoma Cells Displaying MITF/NGFR/IL-8 Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge.

Despite significant advances in targeted therapies against the hyperactivated BRAF/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib, an agent broadly used in combination therapies. Molecular and cellular changes were assessed during alternating periods of trametinib withdrawal and rechallenge in trametinib-resistant cell lines displaying either a differentiation phenotype (MITF/NGFR) or neural crest stem-like dedifferentiation phenotype (NGFR/MITF).