Background & Objectives: New therapy concepts, such as immunotherapy as well as targeted therapy with BRAF and MEK inhibitors, have significantly improved the overall survival of melanoma patients. However, about 20 % of patients do not respond to initial targeted therapy and at the same time, most of the tumors develop resistance through long-term therapy. For particular melanoma subgroups like e.g. the NRAS mutated tumors it is known, that they are associated with aggressive disease, but there is no approved targeted therapy for this subset. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected.
Other clinical studies in breast cancer show that PI3K inhibitors have antitumor activity. This raises the question of whether these inhibitors are also a therapeutic option for melanoma and whether a combination of them with MEK inhibitors could further restrict growth and prevent possible development of resistance in different melanoma subgroups.
Material & Methods: Melanoma cells of different genetic subtypes, as well as tissue slice cultures of patient tumors are treated with BRAF and PI3K inhibitors alone and in combination with MEK inhibitors. In addition to the investigation of cell cytotoxicity and cell cycle remainder, the altered signal transmission is detected. Furthermore, the patient cells are sequenced in order to identify mutations that promote a positive therapeutic response.
Results: BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced ER stress via upregulation of the ER stress-related factors ATF4, CHOP and NUPR1 and the pro-apoptotic protein PUMA. MEKi such as binimetinib induced the expression of the pro-apoptotic protein BIM and activation of the mitochondrial pathway of apoptosis. While the pan-PI3K inhibitor BKM120 is cytotoxic in almost all cell lines and patient cells, the PI3Kα-selective inhibitor BYL719 does not have an antitumour effect. However, the combination of the PI3K inhibitors with the MEK inhibitor already shows a significantly stronger cytotoxic effect at lower concentrations compared to monotherapies.
Conclusion: The data presented herein strongly encourage the clinical use of MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma; the combination of PI3K inhibitors with MEK inhibitors could be a new therapeutic option for BRAF wildtype melanomas.
Through the Athena program, I hope to connect with women in similar positions and stages of life and advance my own career in an independent position by having the opportunity to participate in career planning coaching and future workshops. I also think it is immensely important, especially in today's world, for women in science to form good networks and encourage and promote each other.