Reference Detail

Ref Type

Journal Article

PMID

(31516747)

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer biology & medicine	16	2	2019 May	264-275	Cancer Biol Med

URL

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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 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 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 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 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	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	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