biostudies-literatureUnknown10(9)Hirai N<h4>Background</h4>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 (<i>BRAF</i> 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 <i>BRAF</i> V600E mutation.<h4>Methods</h4>We compared genomic signatures before and after DT treatment in patients with NSCLC.<h4>Results</h4>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 (<i>CDK4</i>). We also found prominent protein expression of <i>CDK4</i> after DT treatment. Induction of <i>CDK4</i> expression in a cell line derived from a patient with the <i>BRAF</i> V600E mutation resulted in partial resistance to dabrafenib.<h4>Conclusions</h4>Our findings suggest a possible relationship between <i>CDK4</i> upregulation and acquired resistance to DT therapy.Translational lung cancer research3737-3744https://www.ebi.ac.uk/biostudies/studies/S-EPMC8512466biostudies-literatureCyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in <i>BRAF</i> V600E-mutated lung cancer.PMC8512466Hatanaka YMinami YOhsaki YHirai NChiba SIUmekage YHatanaka KCOkumura SSasaki TUno YfalseCyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in <i>BRAF</i> V600E-mutated lung cancer.<h4>Background</h4>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 (<i>BRAF</i> 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 <i>BRAF</i> V600E mutation.<h4>Methods</h4>We compared genomic signatures before and after DT treatment in patients with NSCLC.<h4>Results</h4>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 (<i>CDK4</i>). We also found prominent protein expression of <i>CDK4</i> after DT treatment. Induction of <i>CDK4</i> expression in a cell line derived from a patient with the <i>BRAF</i> V600E mutation resulted in partial resistance to dabrafenib.<h4>Conclusions</h4>Our findings suggest a possible relationship between <i>CDK4</i> upregulation and acquired resistance to DT therapy.2021-01-01T00:00:00Z2021 Sep2025-04-04T09:37:26.956Z2025-04-04T09:37:26.956ZS-EPMC85124663473362410.21037/tlcr-21-415