Translational states in NRAS-mutated melanoma preceding resistance to targeted therapy

Despite the existence of an effective targeted therapy option for NRAS-mutant melanoma patients that involves combinatorial inhibition of MEK1/2 and CDK4/6, mechanisms of acquired resistance to these drugs are still unknown. Additional targeting of the PI3K-Akt-mTOR signaling pathway has been reported to be a promising triple combination therapeutic approach to overcome resistance. However, due to the toxic effects of triple-drug combinations, there is a need for further research into drug-resistant phenotypes and strategies to restore tumor sensitivity. For our project, we aim to characterise critical transitions that drive NRAS-mutant melanoma cells to become drug-resistant and reconstruct cell fate trajectories associated with this process.
We interrogated MEK1/2 and CDK4/6 inhibition on several NRAS-mutant melanoma cell lines, including patient-derived metastatic cell lines. By monitoring affected signaling pathways, cell growth, and proliferation, we established NRAS-mutant melanoma cell lines sensitivity to combinatorial MEK1/2 and CDK4/6 inhibition, as well as their transition into a drug-resistant state. Upon prolonged treatment with MEK1/2i plus CDK4/6i cells become either fully drug-resistant or senescent. We performed single-cell RNA sequencing and data analysis at four distinguished time points during treatment to define cell fate decisions and transcriptional states in melanoma under MEK1/2i plus CDK4/6i combinatorial drug exposure. Transitional mechanisms involved cell-cycle arrest, metabolic reprogramming, transport regulation, and EMT process. Our data provide insights on the development of resistance to targeted therapy and contribute towards the identification of the potential novel drug combinations for NRAS-mutant tumors.

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