Published online Sep 15, 2026. doi: 10.4251/wjgo.121282
Revised: May 11, 2026
Accepted: June 12, 2026
Published online: September 15, 2026
Processing time: 158 Days and 14.8 Hours
The development of drug resistance remains a major challenge in clinical practice for patients with gastrointestinal stromal tumors (GISTs).
To investigate whether a cyclin-dependent kinase 6 (CDK6) inhibitor can partially reverse ripretinib-resistant GIST cells and to explore the underlying mechanisms.
Ripretinib-resistant GIST cell lines were established through continuous exposure to increased concentrations of ripretinib. The effects of a CDK6 inhibitor, alone or in combination with ripretinib, on cell viability were evaluated using the Cell Counting Kit-8. Wound healing and invasion indices were used to assess cell migration and invasion capabilities. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression levels of genes and proteins related to the cell cycle, apoptosis, and drug resistance pathways were measured by real-time quantitative polymerase chain reaction and western blot, respectively.
CDK6 was significantly upregulated in ripretinib-resistant GIST cells at both the mRNA and protein levels. The CDK6 inhibitor palbociclib had no significant effect on parental GIST cells but induced G1 phase arrest, promoted apoptosis, and suppressed proliferation in resistant cells. Its combination with ripretinib produced a synergistic effect that reversed ripretinib resistance. Moreover, protein kinase B (AKT) expression and phosphorylation were elevated in resistant cells, and AKT inhibition significantly reduced CDK6 expression. The CDK6 inhibitor also modulated the expression of apoptosis-related proteins (B-cell lymphoma-2-associated X protein, B-cell lymphoma-2, cleaved caspase-9) and cell cycle-related proteins (Cyclin D, p21) in resistant cells.
CDK6 mediates ripretinib resistance in GIST by regulating the AKT signaling pathway. Targeting CDK6 can partially reverse ripretinib-resistant GIST cells. The combination of CDK6 inhibitors and ripretinib represents a promising novel therapeutic strategy for patients with ripretinib-resistant GIST.
Core Tip: This study identifies cyclin-dependent kinase 6 (CDK6) as a key mediator of ripretinib resistance in gastrointestinal stromal tumors (GIST), with its overexpression driven by protein kinase B hyperactivation. CDK6 inhibitor induces G1-phase cell cycle arrest and apoptosis in ripretinib-resistant GIST cells, and combining CDK6 inhibitor palbociclib with ripretinib exerts a synergistic effect to reverse resistance, restoring the tumor cells’ sensitivity to ripretinib. This uncovers the protein kinase B/CDK6 axis as a novel target for treating ripretinib-resistant GIST, providing a new precision therapy strategy.