CDK4/6 Tumor, Abemaciclib, Paclitaxel

Cyclin D-dependent kinases (CDKs) are often activated in human cancer owing to various genetic and epigenetic events. This affects regulatory pathways, and it results in uncontrolled proliferation due to loss of checkpoint integrity. Most tumors show increased activity of CDKs, and this permits escape from senescence during the evolution of malignancy. Among them, cyclin D-CDK4/6-INK4 pathway alterations accelerate G1 progression which provides proliferative and survival advantage to cancer. Therefore, preclinical data demonstrated inhibition of cyclin D-dependent kinase activity have therapeutic benefit. CDK4/6 controls entry into cell cycle progression by regulating Retinoblastoma protein (Rb). The majority of human cancers are known to retain wild-type Rb. In addition, CDK4 amplification and mutations also noted in several tumors. In Rb retained tumors, CDK 4/6 inhibitors reduced Rb phosphorylation and induced G1 arrest. In previous study, CDK4/6 inhibitor showed antitumor activities in Rb-positive breast and colon cancer cell lines. Rapid tumor regression was also noticed in mouse xenograft model. In CDK4 amplified sarcoma cell lines, knockdown of CDK4 inhibited cancer cell proliferation. Cyclin D1 acts with CDK4 and CDK6 to phosphorylate Rb and promote cell-cycle progression, and CDK4/6 inhibitor might be effective for the patients with CCND1/2/3 amplification/mutation or CDK 4/6 amplification. Therefore, basket trial (NCT03310879) is ongoing for the patients with genomic alterations in CCND1, CDKN2A, or CDK4. Amplification/mutation of CCND1/2/3 and CDK4/6 occurs in approximately 15-30% of various solid tumors; sarcoma, GBM, melanoma, gem cell tumor, and gynecologic tumors Regarding the more potent synergistic effect, paclitaxel demonstrated a rationale for promising combination partner with CDK 4/6 inhibitors. In non-small cell lung cancer cell lines, synergistic anti-tumor activities were reported with paclitaxel combination. Corollary, we planned to conduc