BRAF Inhibitor Resistance Mechanisms in Metastatic Melanoma: Spectrum and Clinical Impact

Abstract

Purpose: Multiple BRAF inhibitor resistance mechanisms have been described, however, their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma.Experimental Design: Fifty-nine BRAF V600 -mutant melanoma metastases from patients treated with dabrafenib or vemurafenib were analyzed. The genetic profile of resistance mechanisms and tumor signaling pathway activity was correlated with clinicopathologic features and therapeutic outcomes.Results: Resistance mechanisms were identified in 58% progressing tumors and BRAF alterations were common. Gene expression analysis revealed that mitogen-activated protein kinase (MAPK) activity remained inhibited in 21% of resistant tumors, and the outcomes of patients with these tumors were poor. Resistance mechanisms also occurred in pretreatment biopsies and heterogeneity of resistance mechanisms occurred within patients and within tumors. There were no responses to subsequent targeted therapy, even when a progressing tumor had a resistance mechanism predicted to be responsive.Conclusions: Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required.

Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma

“…Resistance to singleagent BRAF inhibition is acquired predominantly through reactivation of the MAPK pathway. [5][6][7][22][23][24][25][26] Our study shows that the inhibition of the MAPK pathway at two nodes rather than one decreases the risk of progression (and therefore delays resistance) by 25%.…”

“…3,4 Most reported resistance mechanisms reactivate the MAPK pathway. [5][6][7] In addition, BRAF-inhibitor-induced paradoxical activation of the MAPK pathway [8][9][10] can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors. [11][12][13] Independently, singleagent trametinib, a MEK inhibitor, improves the overall survival of patients with BRAF V600 mutation-positive metastatic melanoma, as compared with chemotherapy, and is not associated with paradoxical activation.…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…The elucidation of secondary mechanisms of resistance to BRAF-directed therapies has generated a substantial literature 115 , although larger datasets and meta-analyses have revealed that only a handful of changes underlie the preponderance of genomic resistance mechanisms. In the largest studies to date 20,[116][117][118] , involving 132 samples obtained at the time of clinical resistance, one or more genomic causes of resistance were identified in 58% of patients: NRAS/KRAS mutation in 20%, BRAF splice vari ants in 16%, BRAF amplification in 13%, MEK1/2 mutation in 7%, and non-MAPK-pathway alterations in 11%. Similar resistance mechanisms have been described with combined BRAF-MEK inhibition 119,120 .…”

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

“…These genetic events all share the ability to reactivate ERK signaling. Indeed, reactivated MAPK pathway signaling as measured by ERK transcriptional targets is common in tumor biopsies from BRAF inhibitor-resistant patients (23). Moreover, ERK1/2 reactivation has been observed in the absence of a genetic mechanism of resistance (24,25).…”