Melanoma is the 3rd most common cancer in Australia, and despite significant advancements in treatment for melanoma patients, including both MAPK targeted therapies and immunotherapies, Australia still sees one melanoma-related death every six hours. Therefore, there is an urgent need for novel therapeutic interventions for melanoma patients to improve their prognosis.
One of the biggest problems is therapy resistance. In the context of MAPK targeted therapies, recent evidence highlights how MAPK therapies trigger melanoma cell state transitions, generating a population of drug tolerant persister cells. These cells can adapt and survive within the tumour microenvironment without gaining any additional mutations by seemingly exploiting alternative mRNA processing to promote cellular plasticity and facilitate the emergence of drug tolerance and resistance. Therefore, we hypothesise that melanoma cells are hijacking specific mRNA processing events to promote their adaptation and survival in the face of MAPK targeted therapy. Consequently, understanding and inhibiting these mechanisms could interfere with drug tolerant persister cell formation and ultimately prevent the emergence of drug tolerance and resistance in melanoma altogether.
To investigate whether interfering with aberrant splicing events can effectively disrupt the emergence of drug tolerance, we are investigating inhibiting the clinically relevant splicing factor SF3B1 in combination with MAPK targeted therapies. SF3B1 is a key component of the spliceosome which regulates alternative splicing and consequently, mutated SF3B1 can drive tumorigenic splicing events. Moreover, our previous observations have shown that targeted therapies induce alternative splicing events in drug tolerant melanoma cells lines and patient samples. We have tested multiple cell lines with an SF3B1 inhibitor in combination with MAPK targeted therapies and have observed that splicing inhibition decreases the expression of biomarkers for the four major drug tolerant cell states, including the neural crest stem cell-like state. Notably, this block in adaptive cellular phenotypes coincided with inhibition of multiple major drug tolerant related splicing events observed after MAPK targeted therapies. These findings support that alternative splicing plays a critical role in the development of drug tolerance in response to targeted therapies in melanoma and may offer the possibility for improved outcomes in the treatment of melanoma patients.