A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS

Abstract

The KRAS gain-of-function mutation confers intrinsic resistance to targeted anti-cancer drugs and cytotoxic chemotherapeutic agents, ultimately leading to treatment failure. KRAS mutation frequency in lung adenocarcinoma is ~15–30%. Novel therapeutic strategies should be developed to improve clinical outcomes in these cases. Deregulation of the p16/cyclin-dependent kinase (CDK) 4/retinoblastoma (Rb) pathway is frequently observed in various cancers and it represents an attractive therapeutic target. We compared the anti-tumor efficacy of genetically knocked-down CDK4 and a pharmacological inhibitor of CDK4/6, CINK4, in KRAS mutation-positive lung adenocarcinoma cells. We also investigated changes in anti-proliferative activity and downstream molecules with these treatments in combination with paclitaxel. CDK4 short interfering RNA (siRNA) significantly increased paclitaxel sensitivity in KRAS mutation-positive H23 cells. CINK4 demonstrated concentration- and time-dependent anti-proliferative activity in 5 adenocarcinoma lines. CINK4 induced G1 arrest by downregulating the p16/cyclin D1/Rb pathway, resulting in apoptotic induction via increased expression of cleaved caspase3, cleaved PARP and Bax. Combined CINK4 and paclitaxel produced synergistic anti-proliferative activity and increased apoptosis through reduced cyclin D1 and Bcl-2 in KRAS mutation-positive cancer cells. These data suggest CDK4 is a promising target for development of anti-cancer drugs and CINK4 combined with paclitaxel may be an effective therapeutic strategy for enhancing anti-tumor efficacy in KRAS mutation-positive lung adenocarcinoma.

Cyclin-Dependent Kinase 11 (CDK11) Is Required for Ovarian Cancer Cell Growth In Vitro and In Vivo, and Its Inhibition Causes Apoptosis and Sensitizes Cells to Paclitaxel

“…These results are consistent with studies showing that the addition of CDK2 inhibitor NU6140 to paclitaxel-treated cells resulted in markedly increased cytotoxic effects and apoptotic response in HeLa cervical carcinoma cells (43). A similar study has been found in lung cancer, in which CDK4/6 siRNA or inhibitor significantly enhanced cytotoxicity of paclitaxel in treated cells (44). The results of the phase I clinical trial also showed that the CDK9 inhibitor flavopiridol potentiates chemotherapy agent doxorubicin efficacy in advanced sarcomas (45).…”

Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia

“…Importantly, TP53 is mutated in the T-ALL cell lines that we have studied (34). Similarly, while paclitaxel has been reported to be antagonistic in breast cancer, in some KRAS mutant lung adenocarcinoma cell lines, it has been reported to be synergistic (35). Moreover, there are examples of chemotherapy agents not tested in this study that have been combined with CDK4/6 inhibitors without antagonism between the two drugs, such the case of cytarabine in AML (36) and gemcitabine in a Calu-6 lung cancer xenograft model (37).…”

Direct repression of the oncogene CDK4 by the tumor suppressor miR-486-5p in non-small cell lung cancer

“…In this study, we confirmed that miR-486-5p regulated cell proliferation and cell cycle by directly targeting CDK4. Because CDK4 plays an important role in G1/S phase transition by associating with CDK6 [31-33], deregulation of the CDK4/6 signaling pathway is one of the most common changes found in human cancers [34-36], including NSCLC [37, 38], CDK4/6 were also considered the most desirable targets for cancer therapies [39-41]. …”