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

ABSTRACT:

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.

SUBMITTER: Hirai N 

PROVIDER: S-EPMC8512466 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature