Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on HNSCC

Gilormini, Marion; Malesys, Céline; Armandy, Emma; Manas, Patrick; Guy, Jean‐Baptiste; Magné, Nicolas; Rodriguez-Lafrasse, Claire; Ardail, Dominique

doi:10.18632/oncotarget.7744

Cited by 25 publications

(15 citation statements)

References 63 publications

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“…Similarly, BH3 mimetics that specifically target either BCL-X L or MCL-1 show promise in several hematological malignancies 15–19 . Studies utilizing BH3 mimetics in SCCHN have largely been limited to ABT-737, which reportedly synergizes with cisplatin, etoposide and radiation 20–22 .…”

Section: Introductionmentioning

confidence: 99%

Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck

Carter¹,

Milani²,

Butterworth³

et al. 2019

Cell Death Dis

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Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide, with overall survival of less than 50%. Current therapeutic strategies involving a combination of surgery, radiation, and/or chemotherapy are associated with debilitating side effects, highlighting the need for more specific and efficacious therapies. Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors. In order to explore the therapeutic potential of BH3 mimetics in the treatment of SCCHN, we assessed the expression levels of BCL-2, BCL-XL, and MCL-1 via Western blots and immunohistochemistry, in cell lines, primary cells derived from SCCHN patients and in tissue microarrays containing tumor tissue from a cohort of 191 SCCHN patients. All preclinical models exhibited moderate to high levels of BCL-XL and MCL-1, with little or no BCL-2. Although expression levels of BCL-XL and MCL-1 did not correlate with patient outcome, a combination of BH3 mimetics to target these proteins resulted in decreased clonogenic potential and enhanced apoptosis in all preclinical models, including tumor tissue resected from patients, as well as a reduction of tumor volume in a zebrafish xenograft model of SCCHN. Our results show that SCCHN is dependent on both BCL-XL and MCL-1 for apoptosis evasion and combination therapy targeting both proteins may offer significant therapeutic benefits in this disease.

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Section: Introductionmentioning

confidence: 99%

Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck

Carter¹,

Milani²,

Butterworth³

et al. 2019

Cell Death Dis

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show abstract

“…Combinatory treatment with IR was not examined in clinical trials, yet a precise local treatment by IR in combination with a systemic application of the radiosensitizing Bcl-2/Bcl-xL inhibitor seems exceptionally promising. Several preclinical investigations already demonstrated synergistic effects of BH3-mimetics in combination with IR [ 42 , 44 ]. The effectivity of BH3-mimetica alone or in combination with cytotoxic drugs was also demonstrated in hypoxia in several cancer cells including neuroblastoma, lung and colon carcinoma cells [ 23 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Bcl-2/Bcl-xL inhibitor ABT-263 overcomes hypoxia-driven radioresistence and improves radiotherapy

et al. 2021

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Hypoxia, a characteristic of most human solid tumors, is a major obstacle to successful radiotherapy. While moderate acute hypoxia increases cell survival, chronic cycling hypoxia triggers adaptation processes, leading to the clonal selection of hypoxia-tolerant, apoptosis-resistant cancer cells. Our results demonstrate that exposure to acute and adaptation to chronic cycling hypoxia alters the balance of Bcl-2 family proteins in favor of anti-apoptotic family members, thereby elevating the apoptotic threshold and attenuating the success of radiotherapy. Of note, inhibition of Bcl-2 and Bcl-xL by BH3-mimetic ABT-263 enhanced the sensitivity of HCT116 colon cancer and NCI-H460 lung cancer cells to the cytotoxic action of ionizing radiation. Importantly, we observed this effect not only in normoxia, but also in severe hypoxia to a similar or even higher extent. ABT-263 furthermore enhanced the response of xenograft tumors of control and hypoxia-selected NCI-H460 cells to radiotherapy, thereby confirming the beneficial effect of combined treatment in vivo. Targeting the Bcl-2 rheostat with ABT-263, therefore, is a particularly promising approach to overcome radioresistance of cancer cells exposed to acute or chronic hypoxia with intermittent reoxygenation. Moreover, we found intrinsic as well as ABT-263- and irradiation-induced regulation of Bcl-2 family members to determine therapy sensitivity. In this context, we identified Mcl-1 as a resistance factor that interfered with apoptosis induction by ABT-263, ionizing radiation, and combinatorial treatment. Collectively, our findings provide novel insights into the molecular determinants of hypoxia-mediated resistance to apoptosis and radiotherapy and a rationale for future therapies of hypoxic and hypoxia-selected tumor cell fractions.

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“…As such, ABT-737 could compete with BH3-only proteins for binding to Bcl-XL, Bcl-2 and Bcl-W and thus increase apoptotic priming in cells. ABT-737 showed promise by inducing regression of solid tumours in xenografts of lymphoma and SCLC 45 as well as part of a combination therapy for head and neck squamous cell carcinoma 46 .…”

Section: Exploiting the Apoptotic Landscape Of Cancer For Therapymentioning

confidence: 99%

Emerging approaches to target mitochondrial apoptosis in cancer cells

Gilmore

King

2019

F1000Res

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Apoptosis is a highly conserved programme for removing damaged and unwanted cells. Apoptosis in most cells is coordinated on mitochondria by the Bcl-2 family of proteins. The balance between pro- and anti-apoptotic Bcl-2 family proteins sets a threshold for mitochondrial apoptosis, a balance that is altered during cancer progression. Consequently, avoidance of cell death is an established cancer hallmark. Although there is a general perception that tumour cells are more resistant to apoptosis than their normal counterparts, the realities of cell death regulation in cancer are more nuanced. In this review we discuss how a profound understanding of this control has led to new therapeutic approaches, including the new class of BH3-mimetics, which directly target apoptosis as a vulnerability in cancer. We discuss recent findings that highlight the current limitations in our understanding of apoptosis and how these novel therapeutics work.

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Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on HNSCC

Cited by 25 publications

References 63 publications

Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck

Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck

Bcl-2/Bcl-xL inhibitor ABT-263 overcomes hypoxia-driven radioresistence and improves radiotherapy

Emerging approaches to target mitochondrial apoptosis in cancer cells

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