Eradicating the minimal residual disease in melanoma
Worldwide Cancer Research
Vlaams Instituut voor Biotechnologie
Inhibitors of MAPK signalling have led to unprecedented clinical responses in patients with BRAF-mutant metastatic melanoma. However, the clinical benefit of such agents is limited by genetic alterations that occur (by chance) before or during the treatment, leading to intrinsic or acquired resistance respectively. Additionally, cancer cells can escape the effects of targeted therapy through non-genetic adaptive mechanisms. This is the result of the ability of cancer cells to reversibly switch between drug sensitive, tolerant or resistant phenotypes, owing to cellular plasticity. These clinical observations have highlighted the need for combinations and/or sequential therapies that contend with this “chameleonic” behaviour of cancer cells.  Using single-cell sequencing we find that minimal residual disease (MRD) in melanoma is composed of drug-tolerant populations of persister cells that can harbour both differentiated and de-differentiated phenotypic features. Using trajectory analysis pipelines, we reconstructed the transcriptional dynamic time course and lineage relationships and find that the persister cells are distributed along pseudo-temporally ordering paths with a population of "starved" melanoma cells (or SMCs) that is present at the branching point, preceding both differentiated and de-differentiated end states. These data indicate that drug exposure promotes a rapid and transient switch into a SMC state before persister cells make the decision to move along either a stable differentiation or de-differentiation trajectory. We propose herein to test the hypothesis that transitioning through this SMC state is an early adaptation and critical step for the emergence of both end states and that therapeutic strategies that target these cells will eradicate drug tolerance and, thereby, prevent the acquisition of resistance in a large fraction of melanoma. We will expose SMC vulnerabilities that are amenable to therapeutic intervention using cellular models and test the therapeutic potential of targeting SMCs in the context of rationally designed MRD-directed combination therapies using well-validated pre-clinical models.
5.1 Pharmaceuticals