The biology of BRAF-­‐mutant melanoma and biomarkers of response to targeted therapy

Abstract

After decades of treatment failure, inhibition of the mitogen-activated protein kinase (MAPK) pathway with BRAF inhibitors, either as monotherapy or in combination with MEK inhibitors, have dramatically improved outcomes for patients with BRAF-mutant metastatic melanoma. Rapid and frequent responses occur, but clinical benefit is usually transient because of the emergence of drug resistance. The degree of response and duration of survival is highly variable, with no biomarkers to enable clinicians to predict individual patient response to therapy. This thesis explores the clinical phenotype of BRAF-mutant melanoma, the BRAF mutation status of tumours within metastatic patients, patterns of response and progression to MAPK inhibitors, clinical and molecular biomarkers that may predict response and survival with treatment, and the molecular mechanisms of resistance to treatment. Results show that subtypes of BRAF-mutant melanoma are clinically and biologically distinct, and while the BRAF mutation status within patients is homogeneous, tumour response and disease progression with MAPK inhibitors is markedly heterogeneous within patients. Serum lactate dehydrogenase is the most notable biomarker that predicts for response and survival. Mechanisms of acquired resistance are diverse and heterogeneous, both between and within progressing tumours, and most mechanisms reactivate the MAPK pathway.