PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy

Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC.

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Abstract 61: Overcoming acquired resistance to PI3K inhibitors in head and neck squamous cell carcinoma with combination treatment

10.1158/1557-3265.aacrahns17-61 ◽

2017 ◽

Cited By ~ 1

Author(s):

Aviram Mizrachi ◽

Lara Dunn ◽

Alan Ho ◽

Maurizio Scaltriti

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Combination Treatment ◽

Acquired Resistance ◽

Neck Squamous Cell Carcinoma ◽

Pi3k Inhibitors

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Reduction of Severe Late Toxicity After Definitive Chemoradiation Therapy (CRT) Using Intensity Modulated Radiation Therapy (IMRT) in Non-HPV–Associated Head and Neck Squamous Cell Carcinoma (HNSCC): More than Xerostomia

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2014.05.1629 ◽

2014 ◽

Vol 90 (1) ◽

pp. S535

Author(s):

M.C. Ward ◽

P. Bhateja ◽

C.A. Reddy ◽

D.J. Adelstein ◽

T.B. Bledsoe ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Radiation Therapy ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Intensity Modulated Radiation Therapy ◽

Late Toxicity ◽

Chemoradiation Therapy ◽

Neck Squamous Cell Carcinoma ◽

Intensity Modulated

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Phase I Trial of Copanlisib, a Selective Pi3k Inhibitor, in Combination With Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

10.21203/rs.3.rs-594391/v1 ◽

2021 ◽

Author(s):

Grégoire Marret ◽

Nicolas Isambert ◽

Keyvan Rezai ◽

Jocelyn Gal ◽

Esma Saada-Bouzid ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Phase I ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Maximum Tolerated Dose ◽

Pi3k Inhibitor ◽

Neck Squamous Cell Carcinoma ◽

Best Response ◽

Disease Stabilization

Abstract BackgroundThe phosphatidylinositol-3 kinase pathway is often altered in head and neck squamous cell carcinoma (HNSCC), and is involved in the resistance to EGFR inhibitors. ObjectiveWe investigated the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetics, and preliminary efficacy of the combination of copanlisib, an intravenous, pan-class I PI3K inhibitor, with the anti-EGFR monoclonal antibody cetuximab in recurrent and/or metastatic HNSCC patients in a phase I dose-escalation trial. Patients and methodsCopanlisib was given intravenously on days 1, 8, and 15 of 28-day cycles at the dose of 45 mg and 30 mg, in combination with standard doses of weekly cetuximab (400 mg/m² loading dose followed by 250 mg/m² on days 8, 15, and 22, and weekly thereafter). ResultsThree patients received copanlisib 45 mg, of whom two experienced grade 3 hyperglycemia during Cycle 1 that met the DLT criteria. Eight patients were then treated with copanlisib at the dose of 30 mg. Because of the occurrence of hyperglycemia, a premedication with metformine was introduced on the day of the injections. No DLTs were reported at this dose level. The trial was stopped early because of the unfavourable toxicity profile of the combination. Among eight evaluable patients for response, four patients (50%) had disease stabilization according to RECIST1.1 as best response.ConclusionCopanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients. NCT02822482, Date of registration: June 2016.

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