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: 9.28). 12/2011; 71(23):7137-40. DOI: 10.1158/0008-5472.CAN-11-1243
Source: PubMed

ABSTRACT 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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    • "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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    • "Potentially, antibodies or drugs that neutralize IGF-1, PDGF or other tyrosine kinase receptors could be used to target drug resistant subpopulations that are known to have enhanced IGF1or PDFGF receptor signaling (J. Villanueva, et al., 2011; J. Villanueva, et al., 2010). An alternative approach is to use antibodies such as anti-CD20 or anti-CD133 or anti- CD271 or anti-ABCB5 to deplete respective minor drug resistant subpopulations. "
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