RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

By P. Poulikakos, Yogindra Persaud, M. Janakiraman, X. Kong, Charles Ng, G. Moriceau, Hubing Shi, M. Atefi, B. Titz, M. Gabay and 14 more. Nature, 2011

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Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4–8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS–GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.

Subfields: Computational Theory and Mathematics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/88905b5c9d956f1ce2ee656cf4231748fa1a3f07

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Citations in the corpus

Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress (2018, background): “This line was tested because reported resistant sublines of M397 (M397R) occurred through BRAF alternative splicing (Poulikakos et al., 2011), a resistancemechanism that re-activates theMAPK pathway, and have the same differentiation state as their parental line (Figure 2A).”
Overcoming intrinsic multi-drug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells (2013, background): “…kinase, and insulin growth factor receptor 1 [Nazarian et al., 2010; Villanueva et al., 2010], dimerization of aberrantly spliced BRAF isoforms [Poulikakos et al., 2011], or by secondary genetic events, such as genomic amplification of COT, NRAS mutations, or the MEK1C121S mutation…”
Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. (2013, background): “3C ), consistent with previously described alleles that confer AZD6244 resistance ( 17 ).”
Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity (2020, background): “Vemurafenib Selective BRAF V600E inhibitor (ATP competitive) Activating mutations in NRAS or MEK [23,24]; BRAF/CRAF amplification [23,25]; BRAF alternative splicing [26,27]; RAF heterodimerization [28]; RTK upregulation [29]; Loss of NF1 [30]; COT upregulation [31] Dabrafenib”
Lessons from the cancer genome. (2013, neutral): “Multiple genetic mechanisms of resistance have been described (oncogenicNRASmutations, COT/MAP3K8 gains,BRAF amplification, activatingMEK1mutations, and NF1 loss), each of which produces sustained MAP kinase (ERK) activity in the presence of drug (Emery et al., 2009; Johannessen et al., 2010; Nazari”