Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Abstract

This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo

“…The rebound of phospho‐ERK1/2 in response to single‐agent treatment is maintained for up to 7 days (data not shown). Reactivation of ERK1/2 is consistent with previous reports using vemurafenib or dabrafenib and can occur through multiple, well‐documented mechanisms, including RAF dimerization, 33 MEK amplification, 34 COT expression (in melanoma), 35 RTK overexpression, 35,36 PI3K activation, 37 mutations in RAS , 35 etc., leading to paradoxical reactivation of the pathway 38–40 …”

Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?

“…Intrinsic resistance arises from pre-existing genetic alterations in the tumour or surrounding stromal cells. The molecular mechanisms responsible for the development of intrinsic resistance include increases in proliferative PI3K/AKT and MAPK pathway signalling and disruption to cell cycle regulation [ 17 , 34 , 63 , 64 ].…”

“…Endogenous PTEN mutations are often found in BRAF driven melanomas and at least 10% of PTEN-null BRAF melanomas show intrinsic resistance to BRAF inhibitors. Additionally, mutations in PI3K and AKT which lead to an hyperactivation of the pathway have been described to contribute to resistance to targeted therapy in BRAF melanomas [ 34 , 64 , 65 ].…”

Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas

“…Approximately 60% of melanomas harbor an activating BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutation V600E (changing valine to glutamic acid and being highly predominant over other infrequent BRAF mutations). About 15% of melanomas contain NRAS (neuroblastoma rat sarcoma viral oncogene) mutations [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. In mucosal melanomas, the BRAF and NRAS mutations are infrequent, which may reflect the lack of sunlight exposure [ 13 ].…”

“…Given the importance of driver mutations, targeted drugs were developed to inhibit the aberrant activities of mutated BRAF and NRAS genes. Despite fundamental advances in the development of inhibitors focused on blocking the MAPK pathway in BRAF -mutated cancers, resistance remains a major hurdle to the enduring success of these therapies [ 11 , 16 , 17 , 18 , 19 ].…”