Maintenance BEZ235 Treatment Prolongs the Therapeutic Effect of the Combination of BEZ235 and Radiotherapy for Colorectal Cancer

The PI3K/Akt/mTOR pathway is frequently altered in human papillomavirus (HPV)-positive and negative squamous cell carcinoma of the head and neck (HNSCC) and overstimulation is associated with poor prognosis. PI3K drives Akt activation and constitutive signaling acts pro-proliferative, supports cell survival, DNA repair, and contributes to radioresistance. Since the small molecule NVP-BEZ235 (BEZ235) is a potent dual inhibitor of this pathway, we were interested whether BEZ235 could be an efficient radiosensitizer. The 50 nM BEZ235 was found to abrogate endogenous and irradiation-induced phosphorylation of Akt (Ser473). The anti-proliferative capacity of the drug resulted in an increase in G1-phase cells. Repair of radiation-induced DNA double-strand breaks (DSBs) was strongly suppressed. Reduction in DSB repair was only apparent in G1- but not in G2-phase cells, suggesting that BEZ235 primarily affects non-homologous end joining. This finding was confirmed using a DSB repair reporter gene assay and could be attributed to an impaired phosphorylation of DNA-PKcs (S2056). Cellular radiosensitivity increased strongly after BEZ235 addition in all HNSCC cell lines used, especially when irradiated in the G0 or G1 phase. Our data indicate that targeting the PI3K/Akt/mTOR pathway by BEZ235 with concurrent radiotherapy may be considered an effective strategy for the treatment of HNSCC, regardless of the HPV and Akt status.

Section: Discussionmentioning

confidence: 99%

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining

Schötz

Balzer

Brandt

et al. 2020

“…There was impaired tumour revascularisation likely through the inhibition of HIF-α and VEGF [65,78]. There was inhibited cell migration [48,73,75]. Pathway inhibitors demonstrated the ability to radiosensitise cells growing in the most hypoxic regions of a tumour, which harbour extreme pro-survival and anti-apoptotic mutations [57,64].…”

Section: Sensitising Other Tumour Cells and Endothelial Cells To Radimentioning

confidence: 99%

“…There were multiple different cell lines being used even within a given tumour type. The majority of this research in rectal cancer utilised cell lines or xenograft models derived from colon cancer [18,23,[48][49][50]. However, radiotherapy is only used in the treatment of rectal cancer and not in colon cancer.…”

Section: Limitations Challenges and Potential For Clinical Translationmentioning

confidence: 99%

“…(2) also demonstrated the radiosensitising potential of combined radiotherapy and NVP-BEZ-235 treatment, followed by continued treatment with the drug; in vitro using CRC cell lines HCT 116, HT 29 and SW480, and in vivo using HCT 116 mouse xenografts [48]. This study demonstrated that prolonged treatment after radiotherapy with a dual PI3K/mTOR inhibitor NVP-BEZ235 led to enhanced apoptosis, inhibition of mTOR signalling, prolonged inhibition of cellular viability and disruption of DSB repair pathways.…”

Section: Introductionmentioning

confidence: 98%

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Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors

Wanigasooriya

Tyler

Barros-Silva

et al. 2020

Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.

“…It has become evident that further efforts in colorectal cancer research are required, from providing a better understanding of the cellular and molecular mechanisms leading to colorectal neoplasm initiation and progression from adenoma to metastasis, to generating reliable non-invasive detection tests for identifying lesions at early stages, as well as refining the current therapeutic and personalized approaches and developing new ones. The aim of this Special Issue is to cover all aspects of colorectal cancer research, including basic, preclinical, and clinical approaches.The original articles of this Special Issue present innovative findings toward the design of new strategies that may contribute to the fight against colorectal cancer cells, such as treatments that enhance apoptosis-related mechanisms [1,2], chemosensitivity [3-6] and/or radiotherapy [7], and the characterization of new pathways that lead to the identification of specific biomarkers and/or decipher unique mechanisms underlying colorectal cancer initiation and progression. These mechanisms include the transcriptional regulation of DNA repair proteins [8]; the epigenetic regulation of the zinc finger E-box-binding homeobox 1 [9] and the expression of the (pro)renin receptor [10], , and calcium and calcium-activated potassium channels [12]; the contribution of immune cells in the tumor microenvironment [13]; and the identification of genetic aberrations that occur during the transition from adenoma to carcinoma [14].…”

mentioning

confidence: 99%

Colorectal Cancer Research: Basic, Preclinical, and Clinical Approaches

Beaulieu

2020

Colorectal cancer remains one of the deadliest cancers worldwide. It has become evident that further efforts in colorectal cancer research are required, from providing a better understanding of the cellular and molecular mechanisms leading to colorectal neoplasm initiation and progression from adenoma to metastasis, to generating reliable non-invasive detection tests for identifying lesions at early stages, as well as refining the current therapeutic and personalized approaches and developing new ones. The aim of this Special Issue is to cover all aspects of colorectal cancer research, including basic, preclinical, and clinical approaches.The original articles of this Special Issue present innovative findings toward the design of new strategies that may contribute to the fight against colorectal cancer cells, such as treatments that enhance apoptosis-related mechanisms [1,2], chemosensitivity [3-6] and/or radiotherapy [7], and the characterization of new pathways that lead to the identification of specific biomarkers and/or decipher unique mechanisms underlying colorectal cancer initiation and progression. These mechanisms include the transcriptional regulation of DNA repair proteins [8]; the epigenetic regulation of the zinc finger E-box-binding homeobox 1 [9] and the expression of the (pro)renin receptor [10], , and calcium and calcium-activated potassium channels [12]; the contribution of immune cells in the tumor microenvironment [13]; and the identification of genetic aberrations that occur during the transition from adenoma to carcinoma [14]. The development of tools for preclinical research is also a key research area, such as the establishment of tumor models at the individual patient level [15] and the refinement of clinical approaches for improving the survival of patients with metastatic colorectal cancer [16][17][18][19].Review articles have summarized the latest developments of clinical issues related to the management of improving chemotherapeutic approaches for metastatic colorectal cancer [20][21][22], the characterization of the hallmarks of serrated colorectal lesions [23] and immune-mediated intestinal disorders that can be associated with small bowel carcinoma [24], as well as the current state of knowledge of specific facets of colorectal cancer research such as oncogenic tyrosine kinase signaling [25], integrin α6β4 [26], and epigenetic mechanisms by which long non-coding RNAs regulate gene expression [27].The variety of the content of this Special Issue devoted to colorectal cancer illustrates the need for investigating the cellular basis of this disease from every angle in order to develop efficient screening and treatment strategies that can significantly impact the quality of life of the patients. I would like to thank all of the authors that have contributed to the articles of this Special Issue for their work.