Cancer cell plasticity contributes to the spread of tumours around the body, the ability to resist current therapies and recur post-treatment. This creates a moving target, therefore identifying the mechanisms that underpin plasticity that can be therapeutically targeted is one of the biggest challenges in cancer therapeutics. In melanoma, MAPK targeted therapies trigger a series of cell state transitions that allow cells to survive and become drug tolerant, and accumulating evidence indicates a key role for both transcriptional and post-transcriptional programs. Using high throughput functional screening and transcriptomics approaches we have identified altered mRNA processing as a major mechanism that coordinates regulation of the cellular processes that cause drug tolerance. By assessing mRNA splicing events in melanoma cells treated with MAPK inhibitors, we identified ~2000 exon skipping events indicating large-scale changes in the expression of mRNA transcript variants after therapy. Notable isoform-switching events induced by targeted therapy in melanoma cells were found to occur in genes involved in mitochondrial metabolism, mRNA translation and the ribosome, and mRNA processing. Notably, analysis of matched pre-treatment and on-treatment patient samples confirmed multiple candidate isoform-switching events in melanoma patients treated with MAPK inhibitors. However, the functional significance of these isoform switching events is currently unknown. This has steered our interest towards investigating the potential functions of key isoform-switching events in the response of melanoma cells to targeted therapy. The present study aims to achieve this by generating isoform specific knockouts using CRISPR-Cas13, that targets mRNA instead of DNA. Our analysis of isoform specific functions for candidates of interest will be described in the context of the adaptive response to MAPK targeted therapies.