Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy

Abstract

BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that MAPK reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions, in both core drug escape pathways, were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma re-growth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, co-targeting of two core pathways as an essential strategy for durable responses.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…• Clinical therapeutics for advanced-stage melanoma have improved dramatically with the development of BRAF and MEK inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death protein 1 (PD-1) blocking antibodies, and a modified oncolytic herpes virus that is delivered intratumourally • The overall survival of patients with advanced-stage melanoma has improved from ~9 months before 2011 to an as yet undefined timeframe, with a subset of patients having ongoing long-term tumour control • Melanoma, particularly cutaneous melanoma, is amendable to immunotherapy for various reasons, including extensive tumour infiltration by T cells, a high mutational load, and crosstalk between oncogenic signalling pathways and immunobiology • Resistance mechanisms to BRAF-targeted treatments and immunotherapies are being elucidated; reactivation of the MAPK pathway is common after BRAF inhibition, whereas the effectiveness of both approaches might be limited by loss of tumour antigen presentation and T-cell trafficking • To move the field of clinical therapeutics forward, a greater focus on specific patient populations (based on serum lactose dehydrogenase levels, ECOG performance status, and number of metastases), as well as on landmark progression-free and overall survival measures, will be required in clinical trials occur with or without BRAF, NRAS, or NF1 alterations, but are known to cooperate in driving resistance to BRAF inhibitors in BRAF-mutant melanoma cell lines 19 and biopsy samples of resistant tumours 20,21 .…”

“…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)

“…Genetic mechanisms of acquired resistance to single-agent BRAF inhibition have been intensely studied; some examples of identified resistance mechanisms include splice variants of BRAF (16), BRAF V600E amplification (17), MEK mutations (18), NRAS mutations, and RTK activation (19,20). Resistance mechanisms in the setting of BRAF/MEK inhibitor combination therapy are beginning to emerge and mirror that of BRAF single-agent resistance (21,22).…”

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

“…In melanoma, acquired resistance to systemic treatment appears to be driven by clonal evolution and selection of resistant tumor cells ( 19 ). Repeated biopsies to study genomic alterations resulting from therapies are invasive, can be difficult to obtain, and may be confounded by intratumoral heterogeneity.…”