Palbociclib renders human papilloma virus–negative head and neck squamous cell carcinoma vulnerable to the senolytic agent navitoclax

Nicholas J. Gadsden, Cory D. Fulcher, Daniel Li, Nitisha Shrivastava, Carlos Thomas, Jeffrey E. Segall, Michael B. Prystowsky, Nicolas F. Schlecht, Evripidis Gavathiotis, Thomas J. Ow

Research output: Contribution to journalArticlepeer-review

Abstract

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 (þ) 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 HPVHNSCC cell lines (CAL27, HN31, and PCI15B) and three HPVþ 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 HPVþ 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 b-galactosidase protein expression and BCL-xL protein expression compared with untreated controls in HPV- cells. Co-expression of b-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 HPVHNSCC (CDKN2A disruption) using palbociclib to induce BCL-xL–dependent senescence, which subsequently causes the cancer cells to be vulnerable to the senolytic agent, navitoclax.

Original languageEnglish (US)
Pages (from-to)862-873
Number of pages12
JournalMolecular Cancer Research
Volume19
Issue number5
DOIs
StatePublished - May 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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