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|Ref Type||Journal Article|
|Authors||Zainal NS, Lee BKB, Wong ZW, Chin IS, Yee PS, Gan CP, Mun KS, Rahman ZAA, Gutkind JS, Patel V, Cheong SC|
|Title||Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance.|
|Journal||Cancer biology & medicine|
|Abstract Text||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.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.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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA H1047R||oral squamous cell carcinoma||decreased response||Ribociclib||Preclinical - Cell culture||Actionable||In a preclinical study, oral squamous cell carcinoma cells expressing PIK3CA H1047R demonstrated reduced sensitivity to Kisqali (ribociclib) treatment compared to cells expressing wild-type PIK3CA in culture (PMID: 31516747).||31516747|
|PIK3CA H1047L||oral squamous cell carcinoma||predicted - sensitive||PF-04691502||Preclinical - Cell line xenograft||Actionable||In a preclinical study, PF-04691502 treatment inhibited tumor growth in a cell line xenograft model of oral squamous cell carcinoma harboring PIK3CA H1047L (PMID: 31516747).||31516747|
|PIK3CA H1047L||oral squamous cell carcinoma||decreased response||Palbociclib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, treatment with Ibrance (palbociclib) resulted in sustained tumor growth, but increasing tumor volume over time with treatment in oral squamous cell carcinoma cell line xenograft models harboring PIK3CA H1047L (PMID: 31516747).||31516747|
|PIK3CA H1047R||oral squamous cell carcinoma||decreased response||Abemaciclib||Preclinical - Cell culture||Actionable||In a preclinical study, oral squamous cell carcinoma cells expressing PIK3CA H1047R demonstrated reduced sensitivity to Verzenio (abemaciclib) treatment compared to cells expressing wild-type PIK3CA in culture (PMID: 31516747).||31516747|
|PIK3CA H1047L||oral squamous cell carcinoma||sensitive||Palbociclib + PF-04691502||Preclinical - Cell line xenograft||Actionable||In a preclinical study, oral squamous cell carcinoma cells harboring PIK3CA H1047L demonstrated increased sensitivity to Ibrance (palbociclib) when combined with PF-04691502, and the combination treatment inhibited proliferation in cell culture, and reduced tumor growth in a cell line xenograft model (PMID: 31516747).||31516747|
|PIK3CA H1047R||oral squamous cell carcinoma||resistant||Palbociclib||Preclinical - Cell culture||Actionable||In a preclinical study, oral squamous cell carcinoma cells expressing PIK3CA H1047R demonstrated resistance to Ibrance (palbociclib) treatment in culture (PMID: 31516747).||31516747|