New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

Han, Yongtao; Yu, Xiaopeng; Li, Shuqiang; Liu, Caigang

doi:10.3389/fonc.2020.578095

Cited by 45 publications

(33 citation statements)

References 140 publications

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“…Currently, PARPi are recommended for the treatment of TNBC (olaparib and talazoparib) and epithelial ovarian cancers (olaparib, niraparib, and rucaparib) harboring BRCA1/2 mutations ( 22 ), but their long-term efficacies are variable and independent of the HR status ( 23 , 169 , 170 ). Although, restoration of HR and replication fork stalling are the most common mechanisms of PARPi resistance, HR-independent escape strategies are not rare ( 171 ). Recent work by Fleury et al.…”

Section: Effect Of Tis On the Efficacies Of Immune- And Ddr-directed Therapies In Tnbcmentioning

confidence: 99%

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

et al. 2021

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Triple negative breast cancer (TNBC) is classically treated with combination chemotherapies. Although, initially responsive to chemotherapies, TNBC patients frequently develop drug-resistant, metastatic disease. Chemotherapy resistance can develop through many mechanisms, including induction of a transient growth-arrested state, known as the therapy-induced senescence (TIS). In this paper, we will focus on chemoresistance in TNBC due to TIS. One of the key characteristics of senescent cells is a complex secretory phenotype, known as the senescence-associated secretory proteome (SASP), which by prompting immune-mediated clearance of senescent cells maintains tissue homeostasis and suppresses tumorigenesis. However, in cancer, particularly with TIS, senescent cells themselves as well as SASP promote cellular reprograming into a stem-like state responsible for the emergence of drug-resistant, aggressive clones. In addition to chemotherapies, outcomes of recently approved immune and DNA damage-response (DDR)-directed therapies are also affected by TIS, implying that this a common strategy used by cancer cells for evading treatment. Although there has been an explosion of scientific research for manipulating TIS for prevention of drug resistance, much of it is still at the pre-clinical stage. From an evolutionary perspective, cancer is driven by natural selection, wherein the fittest tumor cells survive and proliferate while the tumor microenvironment influences tumor cell fitness. As TIS seems to be preferred for increasing the fitness of drug-challenged cancer cells, we will propose a few tactics to control it by using the principles of evolutionary biology. We hope that with appropriate therapeutic intervention, this detrimental cellular fate could be diverted in favor of TNBC patients.

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Section: Effect Of Tis On the Efficacies Of Immune- And Ddr-directed Therapies In Tnbcmentioning

confidence: 99%

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

et al. 2021

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“…Given our results, that show extensive redundancy between RAD51AP1 and RAD54, we predict that the simultaneous inactivation of both RAD51AP1 and RAD54 will more significantly sensitize cancer cells to chemotherapy and thereby could lead to the muchwanted reduction in dose with the consequence of diminished side effects. Targeting both RAD51AP1 and RAD54 may be particularly effective against tumors with overactive HDR (Raderschall et al 2002;Xu et al 2005;Klein 2008;Marsden et al 2016), cancerous cells which maintain their telomeres by the ALT pathway (Barroso-Gonzalez et al 2019;Mason-Osann et al 2020;Recagni et al 2020), and BRCA1/2mutant tumors that have regained HDR proficiency and developed resistance to PARPi (Han et al 2020;Kim et al 2021).…”

Section: )mentioning

confidence: 99%

RAD51AP1 and RAD54 underpin two distinct RAD51-dependent routes of DNA damage repair via homologous recombination

Selemenakis

Sharma

Kwon³

et al. 2021

Preprint

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Homology-directed repair (HDR) is a complex DNA damage repair pathway and an attractive target of inhibition in anti-cancer therapy. To develop the most efficient inhibitors of HDR in cells, it is critical to identify compensatory sub-pathways. In this study, we describe the synthetic interaction between RAD51AP1 and RAD54, two structurally unrelated proteins that function downstream of RAD51 in HDR. We show that deletion of both RAD51AP1 and RAD54 synergistically sensitizes human cancer cell lines to treatment with a Poly(adenosine 5'-diphosphate-ribose) polymerase inhibitor, to the DNA inter-strand crosslinking agent mitomycin C, and to hydroxyurea, which stalls the progression of DNA replication. We infer that HDR-directed anti-cancer treatment modalities shall consider this within-pathway functional overlap, and we hypothesize that in cancerous cells the simultaneous inactivation of both RAD54 and RAD51AP1 will accentuate tumor kill.

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“…Two PARP inhibitors (olaparib and talazoparib) have also been approved for TNBC patients with germinal BRCA1/2 mutation. 25 More recently, in 2020, Trodelvy, an antibody‐drug conjugate that links the monoclonal antibody sacituzumab that targets the Trop‐2 protein found in more than 90% of TNBC to the topoisomerase I inhibitor SN‐38 chemotherapy, has also been approved for the treatment of adult patients with metastatic TNBC. 26 Nonetheless, TNBC, which is molecularly, clinically, and histologically heterogeneous, displays extremely severe outcomes compared to all other subtypes of breast cancers because of the lack of relevant drug targets and remains an area of high unmet medical need.…”

Section: Introductionmentioning

confidence: 99%

“…For patients whose tumors are PD‐L1 positive, Tecentriq (atezolizumab) in combination with Abraxane (nab‐paclitaxel) is available under accelerated approval. Two PARP inhibitors (olaparib and talazoparib) have also been approved for TNBC patients with germinal BRCA1/2 mutation 25 . More recently, in 2020, Trodelvy, an antibody‐drug conjugate that links the monoclonal antibody sacituzumab that targets the Trop‐2 protein found in more than 90% of TNBC to the topoisomerase I inhibitor SN‐38 chemotherapy, has also been approved for the treatment of adult patients with metastatic TNBC 26 .…”

Section: Introductionmentioning

confidence: 99%

TH1902, a new docetaxel‐peptide conjugate for the treatment of sortilin‐positive triple‐negative breast cancer

et al. 2021

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New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

Cited by 45 publications

References 140 publications

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

RAD51AP1 and RAD54 underpin two distinct RAD51-dependent routes of DNA damage repair via homologous recombination

TH1902, a new docetaxel‐peptide conjugate for the treatment of sortilin‐positive triple‐negative breast cancer

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