Treatment effect of buparlisib, cetuximab and irradiation in wild-type or PI3KCA-mutated head and neck cancer cell lines

Lattanzio, Laura; Tonissi, Federica; Monteverde, Martino; Vivenza, Daniela; Russi, Elvio; Milano, Gérard; Merlano, Marco; Nigro, Cristiana Lo

doi:10.1007/s10637-015-0210-1

Cited by 36 publications

(38 citation statements)

References 29 publications

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“…One of the most common actionable mutations in HNSCC is PIK3CA that is a component of the PIK3/MTOR/PTEN/AKT signaling pathway involved in regulation of cell survival, growth, proliferation, metabolism, and motility and an attractive drug target in cancer . The phosphoinositide 3‐kinase (PIK3) and mammalian target of rapamycin (MTOR) signaling pathways have been found to have an important role in the pathogenesis of HNSCC and there is evidence that PIK3/MTOR antagonists are active against head and neck cancer cells . Our own studies have confirmed this activity in combination with conventional radiation treatment in low passage xenograft models of HNSCC.…”

Section: Introductionmentioning

confidence: 95%

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

et al. 2019

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Background: The mechanistic target of rapamycin (MTOR) plays a key role in regulating cell growth and metabolism and is commonly overexpressed in head and neck cancer (HNSCC). This study investigated the association of MTOR with clinical outcome in human papilloma virus (HPV) positive and negative HNSCC patients treated by chemoradiation. Methods: A tissue microarray (TMA) consisting of cores from 109 HNSCC patients treated by definitive chemoradiation was constructed and stained with antibodies against p16 and MTOR and expression correlated with clinicopathological features and clinical outcome. Results: MTOR varied widely between tumor cores and was not associated with HPV status or clinicopathological features. There was a positive correlation with pre-treatment FDG uptake.(P = .01). In HPV negative patients, MTOR predicted for shorter locoregional control (P = .02), diseases free survival (P = .02), and overall survival (P = .04).MTOR expression was not associated with outcome in HPV positive patients. Conclusions: Prognostic significance of MTOR expression depends on HPV status.

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Section: Introductionmentioning

confidence: 95%

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

et al. 2019

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“…Over 30 active clinical trials in various phases are investigating PI3K inhibitors for head and neck cancer alone. Two recent entrants BYL719 and BKM120 have resulted in pre-clinical success with on-going trials in multiple solid tumor indications including HNSCC(16–18). While promise remains for PI3K inhibitors, to date there have not been any major clinical successes(19).…”

Section: Introductionmentioning

confidence: 99%

“…While newer generations of both classes with improved toxicology profiles have emerged, the goal here was to evaluate these classes of compounds in the treatment of HNSCC both as single agents and in combination with the standard of care cetuximab. While initial reports had initially indicated that mutations or other alterations along the PI3K/Akt/mTORC axis strongly predicted sensitivity to inhibitors targeting this pathway(12,28), more recent evidence suggests that this relationship is more complex(29,30), and that tumors both with and without such alterations may benefit from the addition of PI3K/mTORC to cetuximab treatment(16). In this work, we test both in vitro and in vivo HNSCC models containing both PI3K/Akt/mTORC altered and unaltered examples, to determine whether the addition of an ATP competitive kinase inhibitor can provide additional antitumor effects.…”

Section: Introductionmentioning

confidence: 99%

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Swick

Prabakaran

Miller

et al. 2017

Molecular Cancer Therapeutics

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Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. To investigate mTORC specific inhibition we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors +/− cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway’s role in driving proliferation. While single agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence suggesting approaches that attempt to match biomarkers to the optimal therapy in HNSCC remains complex and challenging.

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“…As previously reported, unlike in-vivo models, cetuximab exerts a very low antiproliferative effect in cellular models [18,22,23]. It has already been demonstrated that the combination of anti-EGFR therapies and mTOR inhibitors resulted in a stronger growth inhibition in head and neck cancer compared with the two drugs administered alone in vitro [15,16] and in vivo [14,17].…”

Section: Discussionmentioning

confidence: 88%

“…CAL33 cells exhibit high EGFR expression (34 000 fmol/mg protein), carry a mutation on PI3KCA gene exon 20 (c.3140A > G; p. H1047R) and a p53 mutation (codon 175, CGC→CAC), and they have no intrinsic K-ras or B-raf mutations [18]. The cells were routinely maintained as monolayers in regular culture Eagle medium (DMEM) supplemented with 5 mmol/l glutamine, 1 mmol/l sodium pyruvate, and 10% fetal calf serum at 37°C in a 5% CO 2 atmosphere.…”

Section: Cell Linementioning

confidence: 99%

Schedule-dependent interaction between temsirolimus and cetuximab in head and neck cancer

Lattanzio

Milano²,

Monteverde³

et al. 2016

Anti-Cancer Drugs

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Aberrant epidermal growth factor receptor (EGFR) signaling is associated with tumor growth in head and neck squamous cell carcinoma (HNSCC) and is a major focus of targeted therapy. The phosphatidylinositol-3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is frequently mutated in HNSCC and is involved in disease progression and resistance to EGFR inhibitors. The aim of this study was to assess the antiproliferative effects of mTOR inhibition (temsirolimus) combined with the anti-EGFR monoclonal antibody cetuximab, administered according to different combination schedules. Antiproliferative effects of the combination of temsirolimus and cetuximab were determined on the representative HNSCC CAL33 cell line (PI3KCA H1047R mutated and K-RAS wild-type). In addition, key proteins related to the EGFR pathway (pEGFR/EGFR, pAKT/AKT) and the mTOR pathway (p-p70S6K1, p4E-BP1) were determined to explain the cytotoxic effects. Temsirolimus and cetuximab showed a synergistic effect when administered in combination. Supra-additive effect was lost when the two drugs were administered sequentially, irrespective of which drug was administered first. Synergistic effect of the combination was corroborated by a marked downregulation of pEGFR, significant downregulation of pAKT expression, and a marked diminution of p70S6K1 and p4E-BP1 expression. Our study demonstrated a synergistic effect of temsirolimus and cetuximab administered in combination, well illustrated by a simultaneous blockade of intracellular signaling pathways regulating cell proliferation and survival. These results establish the notion of a schedule dependency for the combined treatment, which can be of importance at the clinical level.

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Treatment effect of buparlisib, cetuximab and irradiation in wild-type or PI3KCA-mutated head and neck cancer cell lines

Cited by 36 publications

References 29 publications

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Schedule-dependent interaction between temsirolimus and cetuximab in head and neck cancer

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