Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma

Marín-Béjar, Oskar; Rogiers, Aljosja; Dewaele, Michael; Femel, Julia; Karras, Panagiotis; Poźniak, Joanna; Bervoets, Greet; Raemdonck, Nina Van; Pedri, Dennis; Swings, Toon; Demeulemeester, Jonas; Borght, Sara Vander; Lehnert, Stefan; Bosisio, Francesca Maria; Oord, Joost J. van den; Bempt, Isabelle Vanden; Lambrechts, Diether; Voet, Thierry; Bechter, Oliver; Rizos, Helen; Levesque, Mitchell P.; Leucci, Eleonora; Lund, Amanda W.; Rambow, Florian; Marine, Jean–Christophe

doi:10.1016/j.ccell.2021.05.015

Cited by 97 publications

(105 citation statements)

References 66 publications

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“…Thus, ATF4-mediated phenotype switching might occur early as melanoma cells are adapting to MAPKi therapy. Similarly, the MITF low /NGFR high NCSC-like cells also emerge during early MAPKi treatment ( 16 , 139 ). The MITF high hyperdifferentiated, CD36 + SMC, MITF low /AXL high dedifferentiated, and MITF low /NGFR high NCSC-like populations together make up a reservoir of early MAPKi-persister cells known as minimal residual disease, from which relapse inevitably arises ( Figures 1 , 4 ) ( 16 , 139 ).…”

Section: Melanoma Plasticity Contributes To Therapy Resistancementioning

confidence: 95%

“…Similarly, the MITF low /NGFR high NCSC-like cells also emerge during early MAPKi treatment ( 16 , 139 ). The MITF high hyperdifferentiated, CD36 + SMC, MITF low /AXL high dedifferentiated, and MITF low /NGFR high NCSC-like populations together make up a reservoir of early MAPKi-persister cells known as minimal residual disease, from which relapse inevitably arises ( Figures 1 , 4 ) ( 16 , 139 ). Following the continued dedifferentiation, MITF low /AXL high dedifferentiated and MITF low /NGFR high NCSC-like cells increase in number and often co-emerge within the same tumor ( 16 ).…”

Section: Melanoma Plasticity Contributes To Therapy Resistancementioning

confidence: 95%

“…By eliminating the MITF low /AXL high therapy-tolerant and the MITF high /AXL low therapy-sensitive populations, respectively, enapotamab vedotin combined with MAPK inhibitors or with an anti-PD-1 antibody, cooperatively inhibited melanoma growth in vivo ( 137 , 138 ). Several agents have shown efficacy targeting the MITF low /NGFR high NCSC-like populations, including HSP90 inhibitors ( 103 ), an NGFR kinase inhibitor AG-879 ( 103 ), an RXR antagonist HX531 ( 16 ), and a focal adhesion kinase (FAK) inhibitor PF562271 ( 139 ). As anticipated, blocking the NCSC-like state of cells led to enhanced/restored therapy sensitivity ( 16 , 103 , 139 ).…”

Section: Emerging Strategies To Target Melanoma Plasticity and Their Potential Clinical Impactmentioning

confidence: 99%

“…Several agents have shown efficacy targeting the MITF low /NGFR high NCSC-like populations, including HSP90 inhibitors ( 103 ), an NGFR kinase inhibitor AG-879 ( 103 ), an RXR antagonist HX531 ( 16 ), and a focal adhesion kinase (FAK) inhibitor PF562271 ( 139 ). As anticipated, blocking the NCSC-like state of cells led to enhanced/restored therapy sensitivity ( 16 , 103 , 139 ). The drug-tolerant SMC state is marked by the expression of CD36 ( 16 , 77 ).…”

Section: Emerging Strategies To Target Melanoma Plasticity and Their Potential Clinical Impactmentioning

confidence: 99%

“…Notably, several CD36-blocking agents have been identified and shown anti-tumor activities in different cancer types, including melanoma ( 140 , 141 , 143 ). Building on the concept that redirecting cell state switching might be necessary to achieve optimal therapeutic efficacy, the Marine group went on to show that melanoma lesions escaping a combination of MAPK-targeted therapy (dabrafenib+trametinib) and NCSC-directed therapy (HX531+PF562271) could be further targeted by ERK inhibitors ( 139 ).…”

Section: Emerging Strategies To Target Melanoma Plasticity and Their Potential Clinical Impactmentioning

confidence: 99%

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Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

et al. 2021

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Melanoma is the deadliest form of skin cancer. Although targeted therapies and immunotherapies have revolutionized the treatment of metastatic melanoma, most patients are not cured. Therapy resistance remains a significant clinical challenge. Melanoma comprises phenotypically distinct subpopulations of cells, exhibiting distinct gene signatures leading to tumor heterogeneity and favoring therapeutic resistance. Cellular plasticity in melanoma is referred to as phenotype switching. Regardless of their genomic classification, melanomas switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and often therapy-resistant state. In this review we discuss potential mechanisms underpinning melanoma phenotype switching, how this cellular plasticity contributes to resistance to both targeted therapies and immunotherapies. Finally, we highlight novel strategies to target plasticity and their potential clinical impact in melanoma.

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Section: Melanoma Plasticity Contributes To Therapy Resistancementioning

confidence: 95%

Section: Melanoma Plasticity Contributes To Therapy Resistancementioning

confidence: 95%

Section: Emerging Strategies To Target Melanoma Plasticity and Their Potential Clinical Impactmentioning

confidence: 99%

Section: Emerging Strategies To Target Melanoma Plasticity and Their Potential Clinical Impactmentioning

confidence: 99%

Section: Emerging Strategies To Target Melanoma Plasticity and Their Potential Clinical Impactmentioning

confidence: 99%

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Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

et al. 2021

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The therapeutic potential of targeting minimal residual disease in melanoma

Patel

Somasundram

Smith

et al. 2023

Clinical & Translational Med

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We demonstrate that melanoma responds to targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) in three phases: early response, minimal residual disease (MRD) and disease progression.• The minimal residual disease of both TT and ICI is a nidus for the development of therapeutic resistance and, thus, warrants additional characterization of both tumour cells and their surrounding tumour immune microenvironment.

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Targeting drug‐tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

Song,

Lan,

Zheng

et al. 2023

MedComm

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Drug resistance remains the greatest challenge in improving outcomes for cancer patients who receive chemotherapy and targeted therapy. Surmounting evidence suggests that a subpopulation of cancer cells could escape intense selective drug treatment by entering a drug‐tolerant state without genetic variations. These drug‐tolerant cells (DTCs) are characterized with a slow proliferation rate and a reversible phenotype. They reside in the tumor region and may serve as a reservoir for resistant phenotypes. The survival of DTCs is regulated by epigenetic modifications, transcriptional regulation, mRNA translation remodeling, metabolic changes, antiapoptosis, interactions with the tumor microenvironment, and activation of signaling pathways. Thus, targeting the regulators of DTCs opens a new avenue for the treatment of therapy‐resistant tumors. In this review, we first provide an overview of common characteristics of DTCs and the regulating networks in DTCs development. We also discuss the potential therapeutic opportunities to target DTCs. Last, we discuss the current challenges and prospects of the DTC‐targeting approach to overcome acquired drug resistance. Reviewing the latest developments in DTC research could be essential in discovering of methods to eliminate DTCs, which may represent a novel therapeutic strategy for preventing drug resistance in the future.

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Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma

Cited by 97 publications

References 66 publications

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

The therapeutic potential of targeting minimal residual disease in melanoma

Targeting drug‐tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

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