Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal
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 cy...
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| Format: | Thesis |
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2019
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| Online Access: | http://studentsrepo.um.edu.my/11195/ http://studentsrepo.um.edu.my/11195/4/syafinaz.pdf |
| _version_ | 1848774321494818816 |
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| author | Nur Syafinaz, Zainal |
| author_facet | Nur Syafinaz, Zainal |
| author_sort | Nur Syafinaz, Zainal |
| building | UM Research Repository |
| collection | Online Access |
| description | 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. This study aimed to determine the potency of
palbociclib and identify genetic features that are associated with palbociclib�s response
in OSCC. It was demonstrated that 80% of OSCC cell lines were sensitive to palbociclib
at sub-micromolar concentrations. Palbociclib-treated cells were arrested at G1 phase with
concomitant reduction of phosphorylated-Rb. Consistently, it was found that palbociclib
was effective in controlling tumor growth in mice. Importantly, this study identified
palbociclib-resistant cells to harbour mutations in the PIK3CA gene. Using isogenic cell
lines, PIK3CA-mutant cells were shown to be less responsive to palbociclib compared to
wildtype cells. Despite the reduction of RB phosphorylation upon palbociclib treatment,
PIK3CA-mutant cells upregulated CDK2 and cyclin E1 suggesting this to be the
mechanism underlying resistance to palbociclib. Further, it was demonstrated that the
combination of PF-04691502, a PI3K/mTOR inhibitor, with palbociclib completely
controlled tumor growth in mice. This study provides a rationale for the inclusion of
PIK3CA testing in clinical evaluation of CDK4/6 inhibitors and suggests combination
approaches for further clinical studies. |
| first_indexed | 2025-11-14T13:56:27Z |
| format | Thesis |
| id | um-11195 |
| institution | University Malaya |
| institution_category | Local University |
| last_indexed | 2025-11-14T13:56:27Z |
| publishDate | 2019 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | um-111952022-01-02T22:33:00Z Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal Nur Syafinaz, Zainal RK Dentistry 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. This study aimed to determine the potency of palbociclib and identify genetic features that are associated with palbociclib�s response in OSCC. It was demonstrated that 80% of OSCC cell lines were sensitive to palbociclib at sub-micromolar concentrations. Palbociclib-treated cells were arrested at G1 phase with concomitant reduction of phosphorylated-Rb. Consistently, it was found that palbociclib was effective in controlling tumor growth in mice. Importantly, this study identified palbociclib-resistant cells to harbour mutations in the PIK3CA gene. Using isogenic cell lines, PIK3CA-mutant cells were shown to be less responsive to palbociclib compared to wildtype cells. Despite the reduction of RB phosphorylation upon palbociclib treatment, PIK3CA-mutant cells upregulated CDK2 and cyclin E1 suggesting this to be the mechanism underlying resistance to palbociclib. Further, it was demonstrated that the combination of PF-04691502, a PI3K/mTOR inhibitor, with palbociclib completely controlled tumor growth in mice. This study provides a rationale for the inclusion of PIK3CA testing in clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies. 2019 Thesis NonPeerReviewed application/pdf http://studentsrepo.um.edu.my/11195/4/syafinaz.pdf Nur Syafinaz, Zainal (2019) Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal. Masters thesis, Universiti Malaya. http://studentsrepo.um.edu.my/11195/ |
| spellingShingle | RK Dentistry Nur Syafinaz, Zainal Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal |
| title | Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal |
| title_full | Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal |
| title_fullStr | Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal |
| title_full_unstemmed | Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal |
| title_short | Evaluation of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance / Nur Syafinaz Zainal |
| title_sort | evaluation of palbociclib in oral squamous cell carcinoma and the role of pik3ca in conferring resistance / nur syafinaz zainal |
| topic | RK Dentistry |
| url | http://studentsrepo.um.edu.my/11195/ http://studentsrepo.um.edu.my/11195/4/syafinaz.pdf |