BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS‐mutant melanoma cells: Insights into mode of action and resistance mechanisms

• Published in: International journal of cancer 2024-03, Vol.154 (6), p.1057-1072
• Main Authors: Dinter, Lisa, Karitzky, Paula C., Schulz, Alexander, Wurm, Alexander A., Mehnert, Marie‐Christin, Sergon, Mildred, Tunger, Antje, Lesche, Mathias, Wehner, Rebekka, Müller, Anja, Käubler, Theresa, Niessner, Heike, Dahl, Andreas, Beissert, Stefan, Schmitz, Marc, Meier, Friedegund, Seliger, Barbara, Westphal, Dana
• Format: Article
• Language: English
• Subjects: Antitumor activity; Apoptosis; BRAF; Cancer; Cell culture; Cellular stress response; Drug resistance; Immunology; Immunomodulation; Kinases; Medical research; MEK; MEK inhibitors; Melanoma; Mutants; NRAS mutation; resistance
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.34807

About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid antitumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS‐mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate antitumor activity and also immunological effects in NRAS‐mutant melanoma, providing an ideal backbone for combination treatments. In our study, the MEKi binimetinib, cobimetinib and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS‐mutant melanoma cells using two‐ and three‐dimensional cell culture models as well as RNA sequencing analyses. Furthermore, NRAS‐mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS‐mutant melanoma cells thereby significantly enhancing the antiproliferative and proapoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS‐L, components of antigen‐presenting machinery and the “don't eat me signal” molecule CD47 in the melanoma cells. The BRAFi/MEKi‐resistant, NRAS‐mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen‐activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, our study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS‐mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS‐mutant melanoma. What's new? Patients with NRAS‐mutant melanoma often have aggressive disease requiring rapid intervention. Here, the authors investigated the activity of BRAF/MEK inhibitor combinations in sensitive and resistant NRAS‐mutant melanoma cells. They found that BRAF/MEK inhibitors act in a synergistic manner to inhibit proliferation and activate the mitochondrial pathway of apoptosis in sensitive NRAS‐mutant melanoma cells while also upregulating immune modulatory molecules. Meanwhile, the resistant NRAS‐mutant melanoma cells appear to acquire their resistance by counteracting both the molecular and i