Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS

Abstract

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2)1. Here we characterize a third class of BRAF mutants—those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS–GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition

“…This is the first example of a lineage dependent mechanism of acquired resistance and is due either to the higher level of RTK signaling in CRC than in melanoma or to the increased sensitivity of RTK signaling to ERK-dependent feedback in melanoma compared to CRC. We have recently shown that hypoactive BRAF mutants serve a similar function(32, 33). They amplify ERK signaling in a RAS-dependent manner and, in lung and colon carcinomas, cooperate with upstream RTKs to drive transformation.…”

“…They amplify ERK signaling in a RAS-dependent manner and, in lung and colon carcinomas, cooperate with upstream RTKs to drive transformation. Interestingly, levels of RAS-GTP in melanomas are also not sufficient to cooperate with low activity RAF mutations(33). Tumors with these mutations are invariably found to coexist with NF1 inactivation or RAS mutations.…”

First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study

“…The maximal tumor responses for patients with BRAF non-V600 mutations ( n = 28) are shown in Fig. 4C and are classifi ed by their kinase activity ( 12,40 ). Of note, central nervous system (CNS) responses were seen in a patient with BRAF V600E-mutant lung cancer with metastases, and another with BRAF V600E-mutant glioblastoma mulitforme.…”

Hyperactivation of extracellular signal-regulated kinase (ERK) by RAS-mediated signaling or inhibition of dual specificity phosphatase 6 (DUSP6) is associated with toxicity in lung adenocarcinoma cells with mutations in KRAS or EGFR

“…These factors are likely to include allele-specific attributes of oncogenic mutations in genes such as KRAS 36 and BRAF [36][37][38] ; the cell lineage in which the cancer has arisen 22,37,39 ; the levels of expression of mutant cancer genes 32,38,40,41 ; the co-existence of certain additional mutations 42 ;…”