Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E).

ABSTRACT: The oncogenic BRAF(V600E) mutation activates the ERK1/2 pathway and is detected in 10% of human colorectal cancers (CRCs) where it is associated with poor prognosis. Inhibitors of BRAF have shown only modest efficacy in patients with CRC due to intrinsic drug resistance. We studied the CDK2/CDK9 inhibitor, fadraciclib, alone and in combination with the BRAF inhibitor encorafenib in isogenic human RKO CRC cells with two, one, or no BRAF^V600E alleles (RKO^+/+, A19^+/-, T29^-/-) and in BRAF wild-type HCT-116 cells, including Bax knockout HCT-116^Bax-/- cells. Treatment with fadraciclib was shown to suppress MCL-1 and phospho-MCL-1 (Ser64), induce a Bax-dependent apoptosis, and inhibit colony formation in a BRAF gene dose-dependent manner. Fad

SUBMITTER: Mohiuddin M 

PROVIDER: S-EPMC12329046 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature