The influence of PI3K inhibition on the radiotherapy response of head and neck cancer cells

Glorieux, Mary; Dok, Rüveyda; Nuyts, Sandra

doi:10.1038/s41598-020-73249-z

Cited by 20 publications

(17 citation statements)

References 79 publications

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“…Aberrant upregulation and activation of PI3K/AKT/mTOR pathway is also correlated with resistance radiotherapy. A number of preclinical studies indicated that inhibition of PI3K/AKT/mTOR pathway can sensitize different types of cancer cells, including non-small cell lung cancer, breast cancer, nasopharyngeal carcinoma, oral squamous, and head and neck cancer, to radiotherapy ( Yu et al, 2017 ; Chen et al, 2020b ; Chen et al, 2020c ; Glorieux et al, 2020 ; Schötz et al, 2020 ; Wanigasooriya et al, 2020 ). In breast cancer, IL-6 pre-treatment followed by SIRT1 activation by SRT1720 combined with dual PI3K/mTOR inhibitor NVP-BEZ235 obviously increased sensitivity of the cancer stem cells to radiation, so that late stage breast cancer cells therapeutic effect was effectively improved ( Fatehi et al, 2018 ; Masoumi et al, 2020 ).…”

Section: Pi3k/akt/mtor Pathway Induces Drug Resistance In Breast Cancmentioning

confidence: 99%

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

et al. 2021

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Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.

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Section: Pi3k/akt/mtor Pathway Induces Drug Resistance In Breast Cancmentioning

confidence: 99%

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

et al. 2021

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“…The PI3K pathway limits the effect of RT and chemotherapies by promoting cell survival and DNA repair, and thus PI3K inhibitors could, in principle, potentiate the effect of such therapies. A number of emerging studies, both pre-clinical and clinical, indicate that this may be the case for some PI3K inhibitors in combination with cisplatin and radiotherapy (27,(57)(58)(59)(60)(61).…”

Section: Rtks As Targetsmentioning

confidence: 99%

Targeted Therapy as a Potential De-Escalation Strategy in Locally Advanced HPV-Associated Oropharyngeal Cancer: A Literature Review

Chitsike

Duerksen-Hughes

2021

Front. Oncol.

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The treatment landscape of locally advanced HPV-oropharyngeal squamous cell carcinoma (OPSCC) is undergoing transformation. This is because the high cures rates observed in OPSCC are paired with severe treatment-related, long-term toxicities. These significant adverse effects have led some to conclude that the current standard of care is over-treating patients, and that de-intensifying the regimens may achieve comparable survival outcomes with lower toxicities. Consequently, several de-escalation approaches involving locally advanced OPSCC are underway. These include the reduction of dosage and volume of intensive cytotoxic regimens, as well as elimination of invasive surgical procedures. Such de-intensifying treatments have the potential to achieve efficacy and concurrently alleviate morbidity. Targeted therapies, given their overall safer toxicity profiles, also make excellent candidates for de-escalation, either alone or alongside standard treatments. However, their role in these endeavors is currently limited, because few targeted therapies are currently in clinical use for head and neck cancers. Unfortunately, cetuximab, the only FDA-approved targeted therapy, has shown inferior outcomes when paired with radiation as compared to cisplatin, the standard radio-sensitizer, in recent de-escalation trials. These findings indicate the need for a better understanding of OPSCC biology in the design of rational therapeutic strategies and the development of novel, OPSCC-targeted therapies that are safe and can improve the therapeutic index of standard therapies. In this review, we summarize ongoing research on mechanism-based inhibitors in OPSCC, beginning with the salient molecular features that modulate tumorigenic processes and response, then exploring pharmacological inhibition and pre-clinical validation studies of candidate targeted agents, and finally, summarizing the progression of those candidates in the clinic.

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“…When combined with radiation, BEZ235 was also found to result in strongly enhanced radiosensitivity [31][32][33][34][35][36]. In contrast, for other PI3K-inhibitors such as BKM120 and GDC0980, no such enhancement was obtained [37].…”

Section: Introductionmentioning

confidence: 97%

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Leads to a Synergistic Enhancement of Cisplatin and Radiation in Both HPV-Negative and -Positive HNSCC Cell Lines

Subtil

Gröbner²,

Recknagel³

et al. 2022

Cancers

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The standard of care for advanced head and neck cancers (HNSCCs) is radiochemotherapy, including cisplatin. This treatment results in a cure rate of approximately 85% for oropharyngeal HPV-positive HNSCCs, in contrast to only 50% for HPV-negative HNSCCs, and is accompanied by severe side effects for both entities. Therefore, innovative treatment modalities are required, resulting in a better outcome for HPV-negative HNSCCs, and lowering the adverse effects for both entities. The effect of the dual PI3K/mTOR inhibitor NVP-BEZ235 on a combined treatment with cisplatin and radiation was studied in six HPV-negative and six HPV-positive HNSCC cell lines. Cisplatin alone was slightly more effective in HPV-positive cells. This could be attributed to a defect in homologous recombination, as demonstrated by depleting RAD51. Solely for HPV-positive cells, pretreatment with BEZ235 resulted in enhanced cisplatin sensitivity. For the combination of cisplatin and radiation, additive effects were observed. However, when pretreated with BEZ235, this combination changed into a synergistic interaction, with a slightly stronger enhancement for HPV-positive cells. This increase could be attributed to a diminished degree of DSB repair in G1, as visualized via the detection of γH2AX/53BP1 foci. BEZ235 can be used to enhance the effect of combined treatment with cisplatin and radiation in both HPV-negative and -positive HNSCCs.

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The influence of PI3K inhibition on the radiotherapy response of head and neck cancer cells

Cited by 20 publications

References 79 publications

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

Targeted Therapy as a Potential De-Escalation Strategy in Locally Advanced HPV-Associated Oropharyngeal Cancer: A Literature Review

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Leads to a Synergistic Enhancement of Cisplatin and Radiation in Both HPV-Negative and -Positive HNSCC Cell Lines

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