Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction

Abstract

SUMMARY Combined BRAF and MEK targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. V600EBRAF, expressed at supra-physiological levels because of V600EBRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with over-expressed V600EBRAF via a regulatory interface at R662 of V600EBRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.

Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling

“…These data may explain why DUSP5 is typically retained or even elevated in cells derived from advanced BRAF V600E tumors (25,26). Our results also support a growing body of evidence demonstrating that both normal and tumor cells are under strong selection pressure to maintain ERK activity within a narrow threshold range, such that both ERK inhibition and hyperactivation may cause tumor suppression (14,15,18,41). It is therefore possible that the inhibition or loss of DUSP5 may have beneficial effects in BRAF V600E tumors by causing ERK hyperactivation, as has been demonstrated for DUSP6, whose inhibition or deletion causes senescence in BCR-ABL-driven adult lymphoblastic leukemia (17).…”

“…ERK-inhibitory proteins, such as the MKP/DUSPs, are therefore often assumed to be tumor suppressors, but both decreased and increased MKP/DUSP expression is linked to tumor progression in different contexts (13). These observations may, at least in part, be explained by evidence showing that high-intensity ERK activation in some cell and tumor types engages tumor suppressive mechanisms, such as senescence (14)(15)(16)(17)(18). In such circumstances, the attenuation of ERK signaling by MKP/DUSPs may actually promote tumor progression (16,17).…”

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy

“…Acquired resistance to BRAF and MEK inhibitor therapy combination is also of significant concern with these drugs, and resistance mechanism are similar to mechanisms of resistance to BRAF inhibitors alone, except in greater magnitudes or in combinations such as BRAF ultra-amplification [Long et al 2014a]. Melanoma clones resistant to BRAF and MEK inhibitor therapy also appear to display increased drug addiction compared with those resistant to BRAF inhibitors alone [Moriceau et al 2015].…”

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

“…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). The quest to achieve durable clinical benefit has led researchers to focus on evaluating additional agents that target the downstream MAPK components ERK1/2.…”