Poster Presentation 36th Lorne Cancer Conference 2024

Targeting mRNA processing to overcome resistance in melanoma (#115)

Arwa Alkaraki 1 2 , Susanne Ramm 1 2 , Michael Lee 1 2 , Kaylene Simpson 1 2 , Karen Sheppard 1 2 , Grant McArthur 1 2 , Lorey Smith 1 2 , Cat-Uyen Phan 1 2
  1. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne , Victoria, Australia
  2. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne , Victoria, Australia

Despite significant advancements in treatment strategies that have greatly improved outcomes for melanoma patients, Australia still witnesses one melanoma-related death every six hours. Clearly, there is an urgent need for novel therapeutic options to enhance the prospects of melanoma patients. 

Recent insights from clinical and experimental settings have shed light on how MAPK targeted therapies trigger a sequence of cell state transitions, enabling cells to persist and survive without acquiring new mutations. These resilient cells, known as drug-tolerant cells, appear to exploit altered mRNA processing as a major mechanism for orchestrating the regulation of cellular processes that lead to drug tolerance. Accordingly, we hypothesis that melanoma cells hijack this altered mRNA processing to facilitate adaptation and survival, and targeting this mechanism may thwart the development of resistance. Consequently, testing the clinically available RNA processing inhibitors in combination with targeted therapies could swiftly progress to clinical trials, ultimately improving the overall outcome for melanoma patients.

To investigate whether altering mRNA processing can effectively disrupt the emergence of drug tolerance, we have assessed inhibiting the RNA binding protein RBM39 using the two clinically relevant inhibitors (Indisulam and E7820), in combination with MAPK targeted therapies. RBM39 plays a pivotal role in governing mRNA translation, stability, splicing, and transport. Importantly, our observations have shown that targeted therapies induce alternative splicing of RBM39 in both melanoma cell lines and patient samples. We tested a panel of melanoma cell lines with RBM39 inhibitors in combination with targeted therapies and consistently observed a robust synergy in all cell lines tested. Remarkably, RBM39 inhibitors rescued the expression of drug-tolerant biomarkers and inhibited the invasive phenotype switching observed after MAPK targeted therapies. 

In summary, our findings support that altered RNA processing plays a crucial role during the adaptive response to targeted therapies in melanoma. Importantly, targeting this mechanism impede therapy-induced plasticity, offering new hope for improved outcomes in the treatment of melanoma patients.