Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer.

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.