Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

Almeida, Filipe V.; Douglass, Stephen M.; Fane, Mitchell; Weeraratna, Ashani T.

doi:10.1111/pcmr.12736

Cited by 38 publications

(28 citation statements)

References 119 publications

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“…Analysis of whole-exome sequencing data revealed only a few mutations previously identified as associated with acquired resistance to targeted drugs. It is in line with the current view that in parallel to genetic alterations, melanoma cell-autonomous mechanisms of resistance can rely on complex transcriptomic adaptations supported by epigenetic regulations, including miRNA-mediated mechanisms, and extended by the interplay between tumor and stromal cells that involves cell-cell interactions, paracrine stimulation and extracellular vesicles to create a resistance-permissive niche [39][40][41][42][43][44][45][46]. Mechanisms of resistance primarily directed to support proliferation and survival of cancer cells implicate a plethora of transcriptional regulators, adaptive responses, and feedback loops that extensively affect melanoma cell phenotype enabling the expansion of distinct cell subpopulations in the presence of drug(s) [27,[47][48][49][50][51][52].…”

Section: Discussionsupporting

confidence: 84%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line-and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKT high resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

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Section: Discussionsupporting

confidence: 84%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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“…Of these, 25 increased the frequency of NGFR HIGH /EGFR HIGH cells, while the remaining 36 decreased the frequency. Beyond known factors in melanoma biology such as SOX10 and MITF 26,[30][31][32] , we identified several new factors not previously known to affect resistance to BRAF V600E inhibition. These include DOT1L , which encodes an H3K79 methyltransferase associated with melanoma oncogenesis 33 , and BRD2 , which encodes a protein that is a member of the BET family, often overexpressed in human melanoma 34 .…”

Section: Crispr/cas9 Genetic Screens Identify Factors That Affect Primentioning

confidence: 91%

Genetic screening for single-cell variability modulators driving therapy resistance

Torre

Arai

Bayatpour

et al. 2019

Preprint

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Cellular plasticity describes the ability of cells to transition from one set of phenotypes to another. In the context of cancer therapeutics, plasticity refers to transient fluctuations in the molecular state of tumor cells, driving the formation of rare cells primed to survive drug treatment and ultimately reprogram into a stably resistant fate. However, the biological processes governing this cellular plasticity remain unknown. We used CRISPR/Cas9 genetic screens to reveal genes that affect cell fate decisions by altering cellular plasticity across a range of functional categories. We found that cellular plasticity and cell fate decision making can be decoupled in that factors can affect cell fate decisions in both plasticity-dependent and independent manners. We discovered a novel mode of altering resistance based on cellular plasticity that, contrary to known mechanisms, pushes cells towards a more differentiated state. We further confirmed our prediction that manipulating cellular plasticity before the addition of the main therapy would result in changes in therapy resistance more than concurrent administration. Together, our results indicate that identifying pathways modulating cellular plasticity has the potential to alter cell fate decisions and may provide a new avenue for treating drug resistance.

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“…Nevertheless, a bidirectional crosstalk between CAFs and malignant cells has been firmly established. Highly glycolytic melanoma-associated CAFs can promote melanoma tumor growth in mouse models (Zhang et al 2015a), and have been implicated in promoting resistance to BRAF inhibitor therapy by secretion of hepatocyte growth factor (HGF) (Straussman et al 2012;Almeida et al 2019). Consequently, the ability of therapy to induce melanoma cells to undergo "transdifferentiation" to a CAF-like phenotype is of significant clinical relevance.…”

Section: Exiting the Lineage Through Transdifferentiationmentioning

confidence: 99%

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

2019

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An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.

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Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

Cited by 38 publications

References 119 publications

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Genetic screening for single-cell variability modulators driving therapy resistance

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

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