TY - JOUR
T1 - Palbociclib renders human papilloma virus–negative head and neck squamous cell carcinoma vulnerable to the senolytic agent navitoclax
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.
N1 - Publisher Copyright:
2021 American Association for Cancer Research.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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.
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 (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.
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U2 - 10.1158/1541-7786.MCR-20-0915
DO - 10.1158/1541-7786.MCR-20-0915
M3 - Article
C2 - 33495400
AN - SCOPUS:85105457334
SN - 1541-7786
VL - 19
SP - 862
EP - 873
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 5
ER -