OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations

Riveiro, María E.; Astorgues‐Xerri, Lucile; Vázquez, Ramiro; Frapolli, Roberta; Kwee, Ivo; Rinaldi, Andrea; Odore, Elodie; Rezai, Keyvan; Békradda, Mohamed; Inghirami, Giorgio; D’Incalci, Maurizio; Noel, Kay; Cvitkovic, Esteban; Raymond, Éric; Bertoni, Francesco

doi:10.18632/oncotarget.13181

Cited by 46 publications

(42 citation statements)

References 54 publications

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“…Recently, however, bromodomain and extra‐terminal (BET) inhibitors have emerged as a promising class of drugs that are able to effectively target c‐myc, also in hematological malignancies, including T‐ALL (Abedin, Boddy, & Munshi, ; Loosveld et al, ). However, our unpublished data show that ICG‐001 was more effective in downregulating survivin expression than the clinical‐grade BET inhibitor, OTX‐015 (Riveiro et al, ).…”

Section: Discussionmentioning

confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological disorder that results from the clonal transformation of T‐cell precursors. Phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β‐catenin signaling pathways play a crucial role in T‐cell development and in self‐renewal of healthy and leukemic stem cells. Notably, β‐catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T‐ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β‐catenin pathway through ICG‐001, a CBP/β‐catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK‐474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T‐ALL cells. ICG‐001 and ZSTK‐474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β‐catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐ALL settings.

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Section: Discussionmentioning

confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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“…The antitumor effect of bromodomain inhibitors is not limited to a single cancer type. Besides breast cancer, these compounds have been shown to suppress growth of lung cancer cell lines and sensitize these cells to proapoptotic agents (38,39). However, the efficacy of bromodomain inhibitors for prevention of lung cancer has not been investigated.…”

Section: I-bet 762 Prevents Lung Carcinogenesis In A/j Mice Challengementioning

confidence: 99%

Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762

Zhang

Leal

Carapellucci

et al. 2018

Cancer Prevention Research

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Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells and but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. .

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“…BET targeting has been shown to be effective in acute myeloid leukemia and multiple myeloma (89). A novel BET inhibitor, OTX015 exhibits in vitro anti-tumor activity against NSCLC cell lines harboring different oncogenic mutations (90). SMARCA4/BRG1 is an ATP-dependent catalytic subunit of the SWI/SNF chromatin remodelling complex, best known for its role in malignant rhabdoid tumors.…”

Section: Histone Modification and Chromatin Organizationmentioning

confidence: 99%

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

et al. 2017

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The advent of targeted therapies has established new standards of care for defined molecular subsets of non-small cell lung cancer (NSCLC). Not only has this led to significant changes in the routine clinical management of lung cancer e.g., multiplexed genomic testing, but it has provided important principles and benchmarks for determining "actionability". At present, the clinical paradigms are most evolved for EGFR mutations and ALK rearrangements, where multiple randomized phase III trials have determined optimal treatment strategies in both treatment naïve and resistant settings. However, this may not always be feasible with low prevalence alterations e.g., ROS1 and BRAF mutations. Another emerging observation is that not all targets are equally "actionable", necessitating a rigorous preclinical, clinical and translational framework to prosecute new targets and drug candidates. In this review, we will cover the role of targeted therapies for NSCLC harbouring BRAF, MET, HER2 and RET alterations, all of which have shown promise in non-squamous non-small cell lung cancer (ns-NSCLC). We further review some early epigenetic targets in NSCLC, an area of emerging interest. With increased molecular segmentation of lung cancer, we discuss the upcoming challenges in drug development and implementation of precision oncology approaches, especially in light of the complex and rapidly evolving therapeutic landscape.

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OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations

Cited by 46 publications

References 54 publications

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

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