Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistance
<b>Objective</b> 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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China Anti-Cancer Association
2019-06-01
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| Series: | Cancer Biology & Medicine |
| Subjects: | |
| Online Access: | http://www.cancerbiomed.org/index.php/cocr/article/view/1421 |
| _version_ | 1818316696611454976 |
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| author | Nur Syafinaz Zainal Bernard Kok Bang Lee Zheng Wei Wong Iuan Sheau Chin Pei San Yee Chai Phei Gan Kein Seong Mun Zainal Ariff Abdul Rahman J. Silvio Gutkind Vyomesh Patel Sok Ching Cheong |
| author_facet | Nur Syafinaz Zainal Bernard Kok Bang Lee Zheng Wei Wong Iuan Sheau Chin Pei San Yee Chai Phei Gan Kein Seong Mun Zainal Ariff Abdul Rahman J. Silvio Gutkind Vyomesh Patel Sok Ching Cheong |
| author_sort | Nur Syafinaz Zainal |
| collection | DOAJ |
| description | <b>Objective</b> 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.<b>Methods</b> The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by <i>in vivo</i> evaluation in xenograft models. <i>PIK3CA</i>-mutant isogenic cell lines were used to investigate the effect of <i>PIK3CA</i> mutation towards palbociclib response.<b>Results</b> 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 <i>PIK3CA</i>. Using isogenic cell lines, we showed that <i>PIK3CA</i> 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.<b>Conclusions</b> This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of <i>PIK3CA</i> testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies. |
| first_indexed | 2024-12-13T09:25:32Z |
| format | Article |
| id | doaj.art-0cbed0837b6a4998adfdc5845bbf03bb |
| institution | Directory Open Access Journal |
| issn | 2095-3941 2095-3941 |
| language | English |
| last_indexed | 2024-12-13T09:25:32Z |
| publishDate | 2019-06-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj.art-0cbed0837b6a4998adfdc5845bbf03bb2022-12-21T23:52:38ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412095-39412019-06-0116226427510.20892/j.issn.2095-3941.2018.02572018000257Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistanceNur Syafinaz Zainal0Bernard Kok Bang Lee1Zheng Wei Wong2Iuan Sheau Chin3Pei San Yee4Chai Phei Gan5Kein Seong Mun6Zainal Ariff Abdul Rahman7J. Silvio Gutkind8Vyomesh Patel9Sok Ching Cheong10Head and Neck Team, Cancer Research Malaysia, Selangor 47500, MalaysiaHead and Neck Team, Cancer Research Malaysia, Selangor 47500, MalaysiaHead and Neck Team, Cancer Research Malaysia, Selangor 47500, MalaysiaHead and Neck Team, Cancer Research Malaysia, Selangor 47500, MalaysiaHead and Neck Team, Cancer Research Malaysia, Selangor 47500, MalaysiaHead and Neck Team, Cancer Research Malaysia, Selangor 47500, MalaysiaDepartment of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, MalaysiaDepartment of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, MalaysiaDepartment of Pharmacology, University of California, San Diego 92093-5004, CA, USAHead and Neck Team, Cancer Research Malaysia, Selangor 47500, MalaysiaHead and Neck Team, Cancer Research Malaysia, Selangor 47500, Malaysia<b>Objective</b> 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.<b>Methods</b> The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by <i>in vivo</i> evaluation in xenograft models. <i>PIK3CA</i>-mutant isogenic cell lines were used to investigate the effect of <i>PIK3CA</i> mutation towards palbociclib response.<b>Results</b> 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 <i>PIK3CA</i>. Using isogenic cell lines, we showed that <i>PIK3CA</i> 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.<b>Conclusions</b> This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of <i>PIK3CA</i> testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.http://www.cancerbiomed.org/index.php/cocr/article/view/1421OSCCpalbociclibCDK4/6 inhibitors<i>PIK3CA</i> |
| spellingShingle | Nur Syafinaz Zainal Bernard Kok Bang Lee Zheng Wei Wong Iuan Sheau Chin Pei San Yee Chai Phei Gan Kein Seong Mun Zainal Ariff Abdul Rahman J. Silvio Gutkind Vyomesh Patel Sok Ching Cheong Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistance Cancer Biology & Medicine OSCC palbociclib CDK4/6 inhibitors <i>PIK3CA</i> |
| title | Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistance |
| title_full | Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistance |
| title_fullStr | Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistance |
| title_full_unstemmed | Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistance |
| title_short | Effects of palbociclib on oral squamous cell carcinoma and the role of <i>PIK3CA</i> in conferring resistance |
| title_sort | effects of palbociclib on oral squamous cell carcinoma and the role of i pik3ca i in conferring resistance |
| topic | OSCC palbociclib CDK4/6 inhibitors <i>PIK3CA</i> |
| url | http://www.cancerbiomed.org/index.php/cocr/article/view/1421 |
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