Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy

Smith, Michael P.; Brunton, Holly; Rowling, Emily J.; Ferguson, Jennifer; Arozarena, Imanol; Miskolczi, Zsofia; Lee, Jessica; Girotti, María Romina; Marais, Richard; Levesque, Mitchell P.; Dummer, Reinhard; Frederick, Dennie T.; Flaherty, Keith T.; Cooper, Zachary A.; Wargo, Jennifer A.; Wellbrock, Claudia

doi:10.1016/j.ccell.2016.02.003

Cited by 217 publications

(284 citation statements)

References 46 publications

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“…Nelfinavir, HIV-1 protease inhibitor, was showed as a potent suppressor of PAX3 and MITF expression. Nelfinavir sensitizes BRAF, NRAS and PTEN mutant melanoma cells to MAKP inhibitors (56).…”

Section: Strategies To Overcome Resistancementioning

confidence: 99%

Resistant mechanisms to BRAF inhibitors in melanoma

Manzano¹,

et al. 2016

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Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy.The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them.

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Section: Strategies To Overcome Resistancementioning

confidence: 99%

Resistant mechanisms to BRAF inhibitors in melanoma

Manzano¹,

et al. 2016

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“…Such predictions are increasingly understood as required for rational design of therapies in clinical contexts, where phenotypic heterogeneity and epi-states inducing quiescent cellular states may be the primary driver of persistence and therapy failure across a diverse array of diseases 11,67 . There is a need to consider the selective pressures on alleles that endow cellular populations phenotypic plasticity 19 . Our results provide insight into how, and under what conditions, such phenotypic heterogeneity can provide an initial selective advantage in changing environmental regimes.…”

Section: Discussionmentioning

confidence: 99%

The evolutionary advantage of heritable phenotypic heterogeneity

Carja

Plotkin

2015

Preprint

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Phenotypic plasticity is an evolutionary driving force in diverse biological processes, including the adaptive immune system, the development of neoplasms, and the persistence of pathogens despite drug pressure. It is essential, therefore, to understand the evolutionary advantage of an allele that confers on cells the ability to express a range of phenotypes. Here, we study the fate of a new mutation that allows the expression of multiple phenotypic states, introduced into a finite population of individuals that can express only a single phenotype. We show that the advantage of such a mutation depends on the degree of phenotypic heritability between generations, called phenotypic memory. We analyze the fixation probability of the phenotypically plastic allele as a function of phenotypic memory, the variance of expressible phenotypes, the rate of environmental changes, and the population size. We find that the fate of a phenotypically plastic allele depends fundamentally on the environmental regime. In constant environments, plastic alleles are advantageous and their fixation probability increases with the degree of phenotypic memory. In periodically fluctuating environments, by contrast, there is an optimum phenotypic memory that maximizes the probability of the plastic allele's fixation. This same optimum memory also maximizes geometric mean fitness, in steady state. We interpret these results in the context of previous studies in an infinite-population framework. We also discuss the implications of our results for the design of therapies that can overcome persistence and, indirectly, drug resistance.Perpetual volatility in the surrounding microenvironment, nutrient availability, temperature, immune surveillance, antibiotics or other drugs are realities of life as a microorganism 1-3 . To persist in constantly changing environments and increase resilience, microbial populations often employ mechanisms that expand the range of phenotypes that can be expressed by a given genotype 3, 4 . This form of bet-hedging may not confer an immediate fitness benefit to any one individual, but it can sometimes act to increase the long-term survival and growth of an entire lineage 5,6 .Phenotypic heterogeneity has been well documented both in the context of cellular noise without any known environmental triggers 7 and in the context of persistent environmental challenges 8 . Classic examples include the bifurcation of a genotypically monomorphic population into two phenotypically distinct bistable subpopulations 1 , or phase variation, a reversible switch between different phenotypic states driven by differences in gene expression 3,4,9 . In order to motivate our modeling study, we first describe and compare four clinically relevant examples of phenotypic bet-hedging.One of the most striking examples of evolutionary bet-hedging is bacterial persistence 6, 10-12 , whereby a genetically monomorphic bacterial population survives periods of large antibiotic concentrations by producing phenotypically heterogeneous sub-populations, ...

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“…She commented on her recent publication about MITF as a mechanism of resistance to BRAF inhibitors (20), putting it in context with immunotherapy resistance and its role in the activation of re-expression of ERV sequences. Nelfinavir, an antiretroviral drug, is also a MITF inhibitor that, in combination with BRAF inhibitors, reverses the resistance in melanoma models, in addition, it is also active in NRAS mutated tumors.…”

Section: Inspiring Talksmentioning

confidence: 99%

Report from the II Melanoma Translational Meeting of the Spanish Melanoma Group (GEM)

et al. 2017

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Abstract:The II Melanoma Translational Meeting of the Spanish Melanoma Group (GEM) was held in Barcelona, Spain, at the Hospital Universitari Quiron-Dexeus on November 3 rd , 2016. The conference featured leaders in the fields of oncology, immunology and dermatology, all working at both national and international levels on basic research with direct applications to the clinical setting. The objective was to present cutting edge research on melanoma, mainly from Spanish research groups, but also from some international groups, with the aim of generating a network for future national and international collaborations. During a single day, fifteen speakers, seven biologists and eight clinicians, with a special focus on translational research, outlined the main findings of their ongoing studies. The moderators in every session were recognized GEM oncologists who guided discussion from the clinical point of view regarding the preclinical data presented. Herein, we summarize the main topics discussed during the meeting.

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Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy

Cited by 217 publications

References 46 publications

Resistant mechanisms to BRAF inhibitors in melanoma

Resistant mechanisms to BRAF inhibitors in melanoma

The evolutionary advantage of heritable phenotypic heterogeneity

Report from the II Melanoma Translational Meeting of the Spanish Melanoma Group (GEM)

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