Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations

Abstract

Abstract:The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene. Since the initial identification of the BRAF mutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge. More recently, improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs, such as inhibitors of the downstream effector mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) kinase (MEK). Despite improved success in response rates and in delaying resistance using combination therapy, ultimately, the acquisition of resistance remains a concern. Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies. This review will explore some of the resistance mechanisms, compare what is known in melanoma cancer to colorectal cancer, and discuss strategies under development to manage the development of resistance.

Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma

“…UVB and UVA mutations observed in melanoma are mainly characterized by C→T and G→T transitions, respectively [ 24 , 25 ]. UV-induced PTEN mutations are observed in exons 2 and 6, while germline mutations mainly occur in exon 5; in some cases this protein is deleted, resulting in a loss of its function in 20–40% melanoma cells [ 8 , 13 , 14 , 26 ]. Other mutations observed in MAPK signalling intermediates in melanoma cells include MEK1 (C121S and P124L), MEK2 (Q60P and C125S) and AKT1 (E17K) [ 13 , 27 , 28 ].…”

“…For a short period following treatment, the melanomas regressed and patients had an improved quality of life; however, these tumours become resistant to vemurafenib, eventually resulting in their deaths [ 11 , 12 ]. Resistance to BRAFi has predominantly been shown to be related to the reactivation of the MAPK signalling pathway (BRAF-MEK-ERK–BRAF-MAPK/ERK kinase-extracellular signal-regulated kinase), however, other mechanisms e.g., upregulation of PI3K-AKT-mTOR signalling, increased expression of growth factor receptors on the cell membrane have been shown to be involved [ 13 , 14 ]. It was reported by Rizos et al [ 15 ] that up to 40% of melanoma patients had unidentified mechanisms of resistance.…”

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…One such activating driver mutation is BRAF V600E , a substitution of glutamic acid for valine in codon 600 in exon 15 (7). BRAF mutations have diagnostic and prognostic value in many tumors including not only mucinous ovarian cancer, but also melanoma (11), colorectal cancer (12), thyroid cancer (13), brain tumors and various other cancers (14). Furthermore, the mutation rate in KRAS for proven pathogenic mutations is 60-70% (7).…”

Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma

“…Unfortunately, the initially impressive response rates are limited by the resistance that rapidly and inevitably emerges, with most patients relapsing after long-term treatment [41]. Therefore, understanding the mechanism underlying drug resistance and developing strategies to overcome it is of paramount clinical importance [42]. Given the heterogeneity of melanomas, additional resistance mechanisms are likely to arise, and novel therapeutic strategies will be needed.…”