Background: Combination therapy with the B-Raf inhibitor, dabrafenib, and the MEK inhibitor, trametinib (DT) is commonly used to treat patients with B-Raf proto-oncogene, serine/threonine kinase V600E (BRAF V600E)-mutated non-small cell lung cancer (NSCLC). However, the mechanisms through which cancer develops DT resistance are unclear. Here, we investigated new mechanisms underlying acquired DT-resistant NSCLC with the BRAF V600E mutation.
Methods: We compared genomic signatures before and after DT treatment in patients with NSCLC.
Results: Two of four patients treated with DT developed carcinomatous pleuritis within 3 months. Target DNA sequencing and quantitative polymerase chain reaction (PCR) analyses revealed the increased expression level of cyclin-dependent kinase 4 (CDK4). We also found prominent protein expression of CDK4 after DT treatment. Induction of CDK4 expression in a cell line derived from a patient with the BRAF V600E mutation resulted in partial resistance to dabrafenib.
Conclusions: Our findings suggest a possible relationship between CDK4 upregulation and acquired resistance to DT therapy.
Keywords: B-Raf proto-oncogene, serine/threonine kinase V600E (BRAF V600E); cell cycle; cyclin-dependent kinase 4 (CDK4); dabrafenib; trametinib.
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