PT  - JOURNAL ARTICLE
AU  - Gadsden, Nicholas J.
AU  - Fulcher, Cory D.
AU  - Li, Daniel
AU  - Shrivastava, Nitisha
AU  - Thomas, Carlos
AU  - Segall, Jeffrey E.
AU  - Prystowsky, Michael B.
AU  - Schlecht, Nicolas F.
AU  - Gavathiotis, Evripidis
AU  - Ow, Thomas J.
TI  - Palbociclib Renders Human Papilloma Virus–Negative Head and Neck Squamous Cell Carcinoma Vulnerable to the Senolytic Agent Navitoclax
AID  - 10.1158/1541-7786.MCR-20-0915
DP  - 2021 Jan 25
TA  - Molecular Cancer Research
4099  - http://mcr.aacrjournals.org/content/early/2021/02/16/1541-7786.MCR-20-0915.short
4100  - http://mcr.aacrjournals.org/content/early/2021/02/16/1541-7786.MCR-20-0915.full
AB  - We demonstrate that inhibition of cyclin-dependent kinases 4/6 (CDK4/6) leads to senescence in human papillomavirus (HPV)–negative (−) head and neck squamous cell carcinoma (HNSCC), but not in HPV-positive (+) HNSCC. The BCL-2 family inhibitor, navitoclax, has been shown to eliminate senescent cells effectively. We evaluated the efficacy of combining palbociclib and navitoclax in HPV− HNSCC. Three HPV− HNSCC cell lines (CAL27, HN31, and PCI15B) and three HPV+ HNSCC cell lines (UPCI-SCC-090, UPCI-SCC-154, and UM-SCC-47) were treated with palbociclib. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV− cell lines, whereas HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. In addition, treatment of HPV− cells with palbociclib increased both β-galactosidase protein expression and BCL-xL protein expression compared with untreated controls in HPV− cells. Co-expression of β-galactosidase and BCL-xL occurred consistently, indicating elevated BCL-xL expression in senescent cells. Combining palbociclib with navitoclax led to decreased HPV− HNSCC cell survival and led to increased apoptosis levels in HPV− cell lines compared with each agent given alone.Implications: This work exploits a key genomic hallmark of HPV− HNSCC (CDKN2A disruption) using palbociclib to induce BCL-xL–dependent senescence, which subsequently causes the cancer cells to be vulnerable to the senolytic agent, navitoclax.