SACRAMENTO, CA — The cyclin dependent kinase (CDK) 4/6 pathway appears feasible as a potential target for the treatment of bladder cancer, according to a new study.
A report in the journal Cancer Immunology, Immunotherapy suggested that is especially the case in combination with immunotherapy.1
The study, which was led by University of California Davis researchers and included participation from the VA Northern California Healthcare System in Mather, noted, “Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer.”
To do that, the study team analyzed the genetic alterations of the CDK4/6 pathway in bladder cancer, using The Cancer Genome Atlas database and validated in bladder cancer patient-derived tumor xenografts (PDXs). Researchers treated bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations with the CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms.
The authors pointed out that the combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. In addition, the syngeneic mouse bladder cancer model BBN963 was used to assess how palbociclib could enhance anti-PD1 immunotherapy.
Results indicated that, of the 413 bladder cancer specimens, 79.2% harbored perturbations along the CDK4/6 pathway. Researchers also determined that “palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro.”
In mice carrying PDXs, however, palbociclib treatment was shown to reduce tumor growth and prolong survival from 14 to 32 days compared to vehicle-only controls (p = 0.0001).
“Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs,” the researchers reported. “Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models.”
The authors cautioned that a CDK4/6 inhibitor should not be combined with gemcitabine.
- Long Q, Ma AH, Zhang H, Cao Z, Xia R, Lin TY, Sonpavde GP, de Vere White R, Guo J, Pan CX. Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer. Cancer Immunol Immunother. 2020 Nov;69(11):2305-2317. doi: 10.1007/s00262-020-02609-5. Epub 2020 Jun 6. PMID: 32506263; PMCID: PMC7572640.
