Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Zainal, Nur Syafinaz and Lee, Bernard Kok Bang and Wong, Zheng Wei and Chin, Iuan Sheau and Yee, Pei San and Gan, Chai Phei and Mun, Kein Seong and Rahman, Zainal Ariff Abdul and Silvio Gutkind, J. and Patel, Vyomesh and Cheong, Sok Ching (2019) Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance. Cancer Biology & Medicine, 16 (2). pp. 264-275. ISSN 2095-3941, DOI https://doi.org/10.20892/j.issn.2095-3941.2018.0257.

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Official URL: https://doi.org/10.20892/j.issn.2095-3941.2018.025...


Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma (OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC. Methods: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response. Results: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations. Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin E1 protein levels. We further demonstrated that the combination of a PI3K/mTOR inhibitor (PF-04691502) and palbociclib completely controlled tumor growth in mice. Conclusions: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.

Item Type: Article
Funders: High Impact Research, Ministry of Higher Education (HIR-MOHE) from University of Malaya (Grant No. UM.C/625/1/HIR/MOHE/ DENT-03), Cancer Research Malaysia
Uncontrolled Keywords: OSCC; palbociclib; CDK4/6 inhibitors; PIK3CA
Subjects: R Medicine
Divisions: Faculty of Dentistry
Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 04 Nov 2019 03:23
Last Modified: 04 Nov 2019 03:23
URI: http://eprints.um.edu.my/id/eprint/22928

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