Treatment with BRAF kinase inhibitors leads to rapid resistance and tumor regression in BRAF V600E mutant melanoma patients. However, the underlying mechanism of the developed tumor resistance is not fully clear. In this issue of The EMBO Journal, Kim and colleagues show that melanoma cells acquire resistance to BRAF inhibitors by changing cell shape, modifying their cytoskeleton and, in turn, activating the YAP/TAZ mechanotransduction pathway (Kim et al, 2016).
See also: MH Kim et al (March 2016)
Our way to understand tumor initiation and progression is centered around the notion that cancer is a genetic disease, whereby tumor cells become addicted to specific mutations in “driving” oncogenes that empower novel, often highly aberrant phenotypes. This notion has led to the expectation that blocking the activity of these mutant genes with targeted therapies should ultimately defeat tumors. This ideal scenario, however, clashes with the much grimmer reality of the clinical evidence, as such targeted therapies generally produce mere transient responses that are ultimately overthrown by the emergence of resistant cells dominating the tumor and its metastases (Flaherty et al, 2012). The typical clinical history of melanoma patients is a point in case. A large fraction of melanomas carry activating BRAF mutations, with the majority of these (about 80%) being V600E mutations (Fedorenko et al, 2015). Treatment with BRAF kinase inhibitors, such as PLX4720 (vemurafenib), causes rapid regression of many tumors that invariably recur after few months as refractory to BRAF inhibitors. Such resistance is, in most cases (> 70%), associated to reactivation of MAPK signaling; and yet, resistance still occurs in patients treated with the combination of BRAF and MEK inhibitors (Fedorenko et al, 2015).
So, what is the nature of tumor resistance? Current models …
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