Abstract
Resistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.
Highlights
Stage IV melanoma is the deadliest skin malignancy, with a five-year survival rate of 22.5%
A common set of mechanistic threads likely exists amid the multitude of reports on plasticity and adaptive therapeutic resistance across the melanoma field; a clear and effective strategy to eliminate these persisting minor populations of melanoma cells following targeted and immune therapy remains to be found in most patients
The relatively short progression-free survival (PFS) experienced by most patients treated with either targeted therapy [the 3-year PFS of combinatorial dabrafenib and trametinib therapy is 23% (Schadendorf et al 2017) and the 5-year PFS is 13% (Long et al 2018)] or immunotherapy [pembrolizumab 5-year PFS is 21% (Hamid et al 2019)] suggests that the acquisition of resistance occurs in most patients (Figure 1)
Summary
Keywords neural crest stem cell, plasticity, dedifferentiation, therapy resistance, metastasis
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