Targeting anti-apoptotic BCL-2 family proteins for cancer treatment

Zhang, Xuan; Liu, Xingui; Zhou, Daohong; Zheng, Guangrong

doi:10.4155/fmc-2020-0004

Cited by 22 publications

(15 citation statements)

References 17 publications

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“…For example, two combination treatments (neratinib þ everolimus and neratinib þ palbociclib) share the same apoptosis-related DEPs, including Bcl-XL, Glutamate-D1-2, IRS2, IR-b, phospho-ATR, and MelanA. Bcl-xL and Glutamate-D1-2 are known to be required for apoptosis (59)(60)(61)(62). Increased IR-b expression was also found to induce apoptosis (63).…”

Section: Discussionmentioning

confidence: 99%

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Zhao

Scott

Evans

et al. 2021

Clinical Cancer Research

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Purpose: Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA approved for HER2-overexpressing/amplified (HER2 þ ) breast cancer. In this preclinical study, we explored the efficacy of neratinib in combination with inhibitors of downstream signaling in HER2 þ cancers in vitro and in vivo.Experimental Design: Cell viability, colony formation assays, and Western blotting were used to determine the effect of neratinib in vitro. In vivo efficacy was assessed with patient-derived xenografts (PDX): two breast, two colorectal, and one esophageal cancer (with HER2 mutations). Four PDXs were derived from patients who received previous HER2-targeted therapy. Proteomics were assessed through reverse phase protein arrays and network-level adaptive responses were assessed through Target Score algorithm.Results: In HER2 þ breast cancer cells, neratinib was synergistic with multiple agents, including mTOR inhibitors ever-olimus and sapanisertib, MEK inhibitor trametinib, CDK4/6 inhibitor palbociclib, and PI3Ka inhibitor alpelisib. We tested efficacy of neratinib with everolimus, trametinib, or palbociclib in five HER2 þ PDXs. Neratinib combined with everolimus or trametinib led to a 100% increase in median event-free survival (EFS; tumor doubling time) in 25% (1/4) and 60% (3/5) of models, respectively, while neratinib with palbociclib increased EFS in all five models. Network analysis of adaptive responses demonstrated upregulation of EGFR and HER2 signaling in response to CDK4/6, mTOR, and MEK inhibition, possibly providing an explanation for the observed synergies with neratinib.Conclusions: Taken together, our results provide strong preclinical evidence for combining neratinib with CDK4/6, mTOR, and MEK inhibitors for the treatment of HER2 þ cancer.

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Section: Discussionmentioning

confidence: 99%

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Zhao

Scott

Evans

et al. 2021

Clinical Cancer Research

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“…ABBV-155 (mirzotamab clezutoclax) is the sole ADC under investigation that uses this class of payload and is designed to target tumors expressing CD276. 78 ABBV-155 is being evaluated in a phase I trial for R/R solid tumors alone or in combination with taxane therapy (NCT03595059). RNA polymerase II inhibitors, such as amanitin derivatives, can halt cellular transcription processes and protein synthesis, resulting in apoptosis and cell death.…”

Section: Novel Adcs In Clinical Trialsmentioning

confidence: 99%

Targeting cancer with antibody-drug conjugates: Promises and challenges

Dean

Luo

Twomey

et al. 2021

mAbs

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Antibody-drug conjugates (ADCs) are a rapidly expanding class of biotherapeutics that utilize antibodies to selectively deliver cytotoxic drugs to the tumor site. As of May 2021, the U.S. Food and Drug Administration (FDA) has approved ten ADCs, namely Adcetris®, Kadcyla®, Besponsa®, Mylotarg®, Polivy®, Padcev®, Enhertu®, Trodelvy®, Blenrep®, and Zynlonta™ as monotherapy or combinational therapy for breast cancer, urothelial cancer, myeloma, acute leukemia, and lymphoma. In addition, over 80 investigational ADCs are currently being evaluated in approximately 150 active clinical trials. Despite the growing interest in ADCs, challenges remain to expand their therapeutic index (with greater efficacy and less toxicity). Recent advances in the manufacturing technology for the antibody, payload, and linker combined with new bioconjugation platforms and state-of-the-art analytical techniques are helping to shape the future development of ADCs. This review highlights the current status of marketed ADCs and those under clinical investigation with a focus on translational strategies to improve product quality, safety, and efficacy.

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“…In addition to our core content of reviews, perspectives and original research, the journal also featured content on topical areas of debate relevant to academia and industry, including editorials, commentaries and special reports. Zhang et al, University of Florida, Florida, USA, highlighted methods for targeting the apoptotic pathway in cancer therapy, with a focus on BCL-2 family proteins, in their editorial titled 'Targeting anti-apoptotic BCL-2 family proteins for cancer treatment' [9]. Additionally, Wiederkehr and Santo-Domingo, Nestlé Research, Vaud, Switzerland, discussed the development of next-generation type 2 diabetes drugs in the popular editorial 'Targeting mitochondrial ion channels in type 2 diabetes' [10].…”

Section: Content Highlights Of 2020mentioning

confidence: 99%

Welcome to volume 13 of Future Medicinal Chemistry

Wall

2021

Future Medicinal Chemistry

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Targeting anti-apoptotic BCL-2 family proteins for cancer treatment

Cited by 22 publications

References 17 publications

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Targeting cancer with antibody-drug conjugates: Promises and challenges

Welcome to volume 13 of Future Medicinal Chemistry

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