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| 1 | Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance显示文摘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 PI3 K/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. | 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 | 2019 | Cancer Biology & Medicine2019，16，2： | 3 |
| 2 | Recent developments in the under standing andmanagement ofdiabetic retinopathy显示文摘 | Kein R Klein R | 1988 | Med Clin NorAm1988，72，11： | 1 |
| 3 | Microbiology,chemistry and biofilm development in a pilot drinking water distribution system with copper and plastic pipes显示文摘 | Lehtola MJ Miettinen IT Kein?nen MM | | 0，，17： | 1 |
| 4 | Hearing loss after microvascular decompression for trigeminal neuralgia显示文摘 | Frize W Schafer J Kein H | 1988 | J Neuralgia1988，69，： | 1 |
| 5 | Ozone measurement survey in commercial jet aircraft显示文摘 | Brabets RI Hersh CK Kein MJ | | 0，，： | 1 |
| 6 | Long term observation of intracranial pressure after severe head injury,the phenomenon of secondary head injury显示文摘 | Utenberg A Keining K Schmiedek P | 1993 | Neurosurg1993，32，1： | 1 |
| 7 | Fatty acids of lipid fractions in extracellular polymeric substances of activated sludge flocs显示文摘 | Conrad A Kontro M Kein/inen MM | 2003 | Lipids2003，38，10： | 1 |
| 8 | Audit Committee, Board of Director Characteristics, and Earnings Management 显示文摘 | Kein A | 2002 | Journal of Ac- counting and Economics2002，33，： | 1 |
| 9 | Good continuity of care may improve quality of life in Type 2 diabetes显示文摘 | Hnninen J Takala J Keinnen-Kiukaanniemi S | | 0，，01： | 1 |
| 10 | Cleavage of amyloid peptide dur-ing constitutive processing of its procursor 显示文摘 | Esch FS Kein PS Beattie EC | 1990 | Science1990，248，4959： | 1 |
| 11 | Pitfalls in the echo - Doppler assessnent of diastolic dysfunction 显示文摘 | Grodecki PV Kein AL | 1993 | Echocardiography1993，10，： | 1 |
| 12 | Evaluation of immunoglobulines from plant cells显示文摘 | Kein M B Tang Y Mcleod D A | 1991 | Biotechnol Prog1991，7，： | 1 |
| 13 | Three patterns of catamenial epilepsy显示文摘 | Herzog AG Kein P Ransil BJ | | 0，，10： | 1 |
| 14 | Plastic shrinkage cracking in concrete material,influence of fly ash and fibers显示文摘 | Wang Kein Surendrap | | 0，，06： | 1 |
| 15 | A tetracycline derivative,minocycline,reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window显示文摘 | Yrj(a)nheikki J Tikka T Kein(a)nen R | | 0，，： | 1 |
| 16 | Linking Customer Loyalty to Growth显示文摘 | KEIN INGHAM T L L AKSOY B COOIL T W ANDRE- ASSEN | 2008 | MIT Sloan Management Review2008，49，： | 1 |
| 17 | The contemporary safety and effeetiveness of lower extremity bypass surgeryand peripheral endovascular interventions in the treatment of symptomatic peripheral arterial disease显示文摘 | Tsai T T Rehring T F Rogers R Kein | 2015 | Circulation2015，132，21： | 1 |
| 18 | Metabolic syndrome predisposes to depressive symptoms:a population-based 7-year follow-up study显示文摘 | Koponen H Jokelainen J Keinnen-K | 2008 | J Clin Psychiatry2008，69，2： | 1 |
| 19 | The relationship between hemoglobin levels and diabetic retinopathy显示文摘 | QIAO Q KEINNEN-KIUKAANNIEMI S LAARAE | 1997 | J Clin Epidemiol1997，50，2： | 1 |
| 20 | Flexor tendon healing in vitro:effects of TGF-beta on tendon cell collagen production显示文摘 | Kein MB Yalamanchi N Pham H | 2002 | J Hand Surg Am2002，27，4： | 1 |
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