Resistance to BRAF Inhibitors: Unraveling Mechanisms and Future Treatment Options

Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Cancer Research (Impact Factor: 9.33). 12/2011; 71(23):7137-40. DOI: 10.1158/0008-5472.CAN-11-1243
Source: PubMed


The mitogen-activated protein kinase (MAPK) pathway has emerged as a central target for melanoma therapy due to its persistent activation in the majority of tumors. Several BRAF inhibitors aimed at curbing MAPK pathway activity are currently in advanced stages of clinical investigation. However, their therapeutic success is limited by the emergence of drug resistance, as responses are transient and tumors eventually recur. To develop effective and long-lasting therapies for melanoma patients, it is essential to understand the mechanisms underlying resistance to BRAF inhibitors. Here, we briefly review recent preclinical studies that have provided insight into the molecular mechanisms of resistance to BRAF inhibitors and discuss potential strategies to treat drug-resistant melanomas.

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    • "Given that combined V600EBRAF-mTOR inhibition was insufficient to attenuate p-rpS6, and coupled with the observation that PI3K activity and downstream signaling has been proposed as a mechanism of resistance to BRAF inhibition in colorectal cancer [22] and melanoma [23], [24], we evaluated the effects of dual PI3K-mTOR inhibition in COLO 205 cells in conjunction with V600EBRAF inhibition (Fig. 6). COLO 205 cells were treated with either PLX4032, BEZ235, a small molecule dual inhibitor of PI3K and mTOR [25], or the combination for 24 hours. "
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    ABSTRACT: Biomarkers that predict response to targeted therapy in oncology are an essential component of personalized medicine. In preclinical treatment response studies that featured models of wild-type KRAS or mutant BRAF colorectal cancer treated with either cetuximab or vemurafenib, respectively, we illustrate that [18F]-FLT PET, a non-invasive molecular imaging readout of thymidine salvage, closely reflects pro-survival responses to targeted therapy that are mediated by PI3K-mTOR activity. Activation of pro-survival mechanisms forms the basis of numerous modes of resistance. Therefore, we conclude that [18F]-FLT PET may serve a novel and potentially critical role to predict tumors that exhibit molecular features that tend to reflect recalcitrance to MAPK-targeted therapy. Though these studies focused on colorectal cancer, we envision that the results may be applicable to other solid tumors as well.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Activating mutations in BRAF (mainly V600E/K) have been identified in half of all melanoma cases [4], and the development of novel compounds targeting mutated BRAF [6], [19], or compounds boosting the immunological responses directed towards cancer cells [20], has given new hope to this group of patients. However, these studies have also revealed that early drug resistance occurs in the majority of patients, causing a considerable clinical challenge [2], [5], [6]. As kinases are part of key cellular process, and mutations herein are often implicated in both cancer progression and/or drug resistance [21], we examined the overall kinase activity profiles in metastatic malignant melanoma tumor samples, using a multiplex microarray technology previously proven to be robust and reliable [22]–[25]. "
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    ABSTRACT: Treatment of metastatic malignant melanoma patients harboring BRAF(V600E) has improved drastically after the discovery of the BRAF inhibitor, vemurafenib. However, drug resistance is a recurring problem, and prognoses are still very bad for patients harboring BRAF wild-type. Better markers for targeted therapy are therefore urgently needed. In this study, we assessed the individual kinase activity profiles in 26 tumor samples obtained from patients with metastatic malignant melanoma using peptide arrays with 144 kinase substrates. In addition, we studied the overall ex-vivo inhibitory effects of vemurafenib and sunitinib on kinase activity status. Overall kinase activity was significantly higher in lysates from melanoma tumors compared to normal skin tissue. Furthermore, ex-vivo incubation with both vemurafenib and sunitinib caused significant decrease in phosphorylation of kinase substrates, i.e kinase activity. While basal phosphorylation profiles were similar in BRAF wild-type and BRAF(V600E) tumors, analysis with ex-vivo vemurafenib treatment identified a subset of 40 kinase substrates showing stronger inhibition in BRAF(V600E) tumor lysates, distinguishing the BRAF wild-type and BRAF(V600E) tumors. Interestingly, a few BRAF wild-type tumors showed inhibition profiles similar to BRAF(V600E) tumors. The kinase inhibitory effect of vemurafenib was subsequently analyzed in cell lines harboring different BRAF mutational status with various vemurafenib sensitivity in-vitro. Our findings suggest that multiplex kinase substrate array analysis give valuable information about overall tumor kinase activity. Furthermore, intra-assay exposure to kinase inhibiting drugs may provide a useful tool to study mechanisms of resistance, as well as to identify predictive markers.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "Around 50% of melanomas bear activating mutations in BRAF (Davies et al., 2002), whereas a further 15%–20% express activated NRAS (van Elsas et al., 1995), and a lower proportion activation of MEK (Nikolaev et al., 2012), or other factors that activate MAPK signaling such as Kit (Curtin et al., 2006) or GNAQ (Van Raamsdonk et al., 2009). Consistent with genetic heterogeneity playing a major role in therapeutic resistance, targeting activated BRAF with vemurafenib leads to dramatic and rapid tumor regression that relapses after some months (Sosman et al., 2012; Villanueva et al., 2011), with resistance arising from activating mutations in other factors that bypass the requirement for activated BRAF in MAPK signaling (Fedorenko et al., 2011; Nazarian et al., 2010). Although combining BRAF inhibition with molecules that target other components of the MAPK pathway is currently being investigated (Smalley and Flaherty, 2009), it is clear that even for targeted therapies, genetic heterogeneity represents a major challenge to effective therapy. "
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    ABSTRACT: Therapeutic resistance in melanoma and other cancers arises via irreversible genetic, and dynamic phenotypic, heterogeneity. Here, we use directed phenotype switching in melanoma to sensitize melanoma cells to lineage-specific therapy. We show that methotrexate (MTX) induces microphthalmia-associated transcription factor (MITF) expression to inhibit invasiveness and promote differentiation-associated expression of the melanocyte-specific Tyrosinase gene. Consequently, MTX sensitizes melanomas to a tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), that inhibits the essential enzyme DHFR with high affinity. The combination of MTX and TMECG leads to depletion of thymidine pools, double-strand DNA breaks, and highly efficient E2F1-mediated apoptosis in culture and in vivo. Importantly, this drug combination delivers an effective and tissue-restricted antimelanoma therapy in vitro and in vivo irrespective of BRAF, MEK, or p53 status.
    Full-text · Article · Jun 2013 · Cancer cell
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