Reference Detail

Ref Type

Journal Article

PMID

(26589432)

Authors

Zumsteg ZS, Morse N, Krigsfeld G, Gupta G, Higginson DS, Lee NY, Morris L, Ganly I, Shiao SL, Powell SN, Chung CH, Scaltriti M, Baselga J

Title

Taselisib (GDC-0032), a Potent β-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	8	2016 Apr 15	2009-19	Clin Cancer Res

URL

Abstract Text

ActivatingPIK3CAgenomic alterations are frequent in head and neck squamous cell carcinoma (HNSCC), and there is an association between phosphoinositide 3-kinase (PI3K) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110α, in combination with radiation in HNSCC.The efficacy of GDC-0032 was assessedin vitroin 26 HNSCC cell lines with crystal violet proliferation assays, and changes in PI3K signaling were measured by Western blot analysis. Cytotoxicity and radiosensitization were assessed with Annexin V staining via flow cytometry and clonogenic survival assays, respectively. DNA damage repair was assessed with immunofluorescence for γH2AX foci, and cell cycle analysis was performed with flow cytometry.In vivoefficacy of GDC-0032 and radiation was assessed in xenografts implanted into nude mice.GDC-0032 inhibited potently PI3K signaling and displayed greater antiproliferative activity in HNSCC cell lines withPIK3CAmutations or amplification, whereas cell lines withPTENalterations were relatively resistant to its effects. Pretreatment with GDC-0032 radiosensitizedPIK3CA-mutant HNSCC cells, enhanced radiation-induced apoptosis, impaired DNA damage repair, and prolonged G2-M arrest following irradiation. Furthermore, combined GDC-0032 and radiation was more effective than either treatment alonein vivoin subcutaneous xenograft models.GDC-0032 has increased potency in HNSCC cell lines harboringPIK3CA-activating aberrations. Further, combined GDC-0032 and radiotherapy was more efficacious than either treatment alone inPIK3CA-altered HNSCCin vitroandin vivo This strategy warrants further clinical investigation.

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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	head and neck squamous cell carcinoma	sensitive	Radiotherapy + Taselisib	Preclinical	Actionable	In a preclinical study, Taselisib (GDC-0032) enhanced the effects of radiation induced apoptosis of head and neck squamous carcinoma cells harboring PIK3CA H1047R (PMID: 26589432).	26589432
PTEN del	head and neck squamous cell carcinoma	resistant	Taselisib	Preclinical	Actionable	In a preclinical study, head and neck squamous cell carcinoma cells homozygous for PTEN deletion were resistant to Taselisib (GDC-0032) in culture (PMID: 26589432).	26589432
PIK3CA mutant	head and neck squamous cell carcinoma	sensitive	Radiotherapy + Taselisib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Taselisib (GDC-0032) enhanced the effects of radiation induced apoptosis in HNSCC cell lines, cell line xenograft models, and a patient derived xenograft (PDX) model, all with PIK3CA mutations (PMID: 26589432).	26589432
PIK3CA amp	head and neck squamous cell carcinoma	sensitive	Radiotherapy + Taselisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Taselisib (GDC-0032) enhanced the effects of radiation induced apoptosis in HNSCC cell lines and cell line xenograft models with PIK3CA amplification (PMID: 26589432).	26589432
PTEN mutant	head and neck squamous cell carcinoma	resistant	Taselisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, head and neck squamous cell carcinoma cell lines and cell line xenograft models with PTEN alterations were resistant to the apoptotic effects of Taselisib (GDC-0032) (PMID: 26589432).	26589432