Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations

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.

Keywords: BRAF; acquired resistance.

Figure 1

RAS/RAF/MEK aberrant signaling and mechanisms of resistance to inhibition in melanoma. Oncogenic BRAFV600E cells become independent from external growth factors (GF) (triangle symbol marked with a X) and other stimuli leading to constitutive activation of the MAPK pathway. Increased MAPK signalling (four arrows) eventually leads to enhanced gene expression including MAP kinase phosphatases (DUSPs) and sprouty proteins (SPRYs). Despite elevation of those important inhibitory regulators (T lines) of the MAPK pathway, tumour cells adapt and rely on neighbour pathways, such as the PI3K pathway, to grow and survive, Furthermore, negative inhibitory mechanisms of the MAPK pathway, including inactivation of BRAF via ERK1/2, are now lessened (faded T) due to conformational changes in the BRAF. Conferred mechanisms of resistance to BRAF inhibitors including up-regulation of PDGFRB, RAS mutations, elevation of CRAF, BRAFV600E amplification, alternative splicing of BRAFV600E, elevation of COT (MAP3K8), MEK mutation, PTEN loss, PI3K and AKT mutations were highlighted in green.