Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

By R. Nazarian, Hubing Shi, Qi Wang, X. Kong, R. Koya, Hane Lee, Zugen Chen, Mi-Kyung Lee, N. Attar, H. Sazegar and 6 more. Nature, 2010

2,217 citations recorded by the source corpus.

Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/27f7779851b2160301f32a58680aa2bf20a63bff

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Citations in the corpus

Primary resistance to PD-1 blockade mediated by JAK1/2 mutations (2016, methodology): “Samples were immediately fixed in formalin followed by paraffin embedding, and when there was additional sterile piece of the tumor processed for snapfreezing in liquid nitrogen and to establish a cell line as previously described (33-35).”
Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “…carrying V600E BRAF mutations become resistant to the BRAF inhibitor vemurafenib through a variety of genetic mechanisms (Johannessen et al., 2010; Nazarian et al., 2010; Poulikakos et al., 2011; Poulikakos and Rosen, 2011; Villanueva et al., 2010), and we are unable to find any evidence that…”
The Ras-ERK and PI3K-mTOR Pathways: Cross-talk and Compensation (2011, background): “Conversely, analysis of tumor biopsies from phase I clinical trials with an mTORC1 inhibitor revealed an upregulation of ERK activity in metastatic breast cancer patients [97].”
Dynamic Reprogramming of the Kinome In Response to Targeted MEK Inhibition In Triple Negative Breast Cancer (2012, positive): “For example, RTK upregulation has been observed following targeted inhibition of selective kinases (Chandarlapaty et al., 2011; Johannessen et al., 2010; Nazarian et al., 2010; Villanueva et al., 2010); this kinome reprogramming circumvents inhibition of protooncogenic kinases.”