ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

Jette, Nicholas; Radhamani, Suraj; Ye, Ruiqiong; Yu, Yaping; Arthur, Greydon; Goutam, Siddhartha; Bismar, Tarek A.; Kumar, Mehul; Bose, Pinaki; Yip, Steven; Kolinsky, Michael; Lees‐Miller, Susan P.

doi:10.1007/s42764-020-00011-0

Cited by 11 publications

(5 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A study reported the effectiveness of AZD6738 in inducing cell death in olaparib-treated ATM-deficient cancer cells while exerting a low effect on ATM-proficient control cells. They suggested that the co-administration of PARP and ATR inhibitors may be useful for the treatment of cancer types that show deficiency in ATM [ 153 ].…”

Section: Other Promising Inhibitors Of Pancreatic Cancermentioning

confidence: 99%

Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond

Shetu

James

Rivera

et al. 2023

CIMB

View full text Add to dashboard Cite

Pancreatic enzymes assist metabolic digestion, and hormones like insulin and glucagon play a critical role in maintaining our blood sugar levels. A malignant pancreas is incapable of doing its regular functions, which results in a health catastrophe. To date, there is no effective biomarker to detect early-stage pancreatic cancer, which makes pancreatic cancer the cancer with the highest mortality rate of all cancer types. Primarily, mutations of the KRAS, CDKN2A, TP53, and SMAD4 genes are responsible for pancreatic cancer, of which mutations of the KRAS gene are present in more than 80% of pancreatic cancer cases. Accordingly, there is a desperate need to develop effective inhibitors of the proteins that are responsible for the proliferation, propagation, regulation, invasion, angiogenesis, and metastasis of pancreatic cancer. This article discusses the effectiveness and mode of action at the molecular level of a wide range of small molecule inhibitors that include pharmaceutically privileged molecules, compounds under clinical trials, and commercial drugs. Both natural and synthetic small molecule inhibitors have been counted. Anti-pancreatic cancer activity and related benefits of using single and combined therapy have been discussed separately. This article sheds light on the scenario, constraints, and future aspects of various small molecule inhibitors for treating pancreatic cancer—the most dreadful cancer so far.

show abstract

Section: Other Promising Inhibitors Of Pancreatic Cancermentioning

confidence: 99%

Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond

Shetu

James

Rivera

et al. 2023

CIMB

View full text Add to dashboard Cite

show abstract

“…The combination of PARP inhibitors with some targeted agents is also a potential strategy. In research on ATM alterations, preclinical data showed that olaparib induced reversible G 2 arrest but was not cytotoxic in ATM-deficient cell lines [77,78]. Clinical data also showed that few patients with ATM alterations were sensitive to PARP inhibitors [13,28].…”

Section: Targeted Agentsmentioning

confidence: 99%

“…It is necessary to explore other therapies in patients with ATM alterations [79]. Preclinical studies found that the combination of olaparib and an ATR inhibitor could induce cell death in ATM-deficient cells [77,78]. This was considered to be mediated by the ablation of G 2 arrest induced by ATR inhibitors.…”

Section: Targeted Agentsmentioning

confidence: 99%

Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer

et al. 2021

View full text Add to dashboard Cite

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.

show abstract

“…Response rates to PARPis in ATM-deficient tumor cell lines were seen in chronic lymphocytic leukemia [28], gastric cancer [63], and mantle cell lymphoma [64]. However, other studies revealed ATM deficiency may not be enough to fully sensitize these cells to PARP inhibition; experiments showed olaparib given alone to ATM-deficient cancer cells induced only a cytostatic state, while there are emerging data suggesting that olaparib combined with an ATR (ATM-and RAD3-related) inhibitor provides an additional cytotoxic effect [65,66]. A study using prostate cancer cell lines agreed that ATM loss may not respond to PARPis, but they did respond well to an ATR inhibitor [67].…”

Section: Looking Into the Future: Potential Biomarkers Of Response To Parp Inhibitors Cautious Optimism And Ongoing Clinical Trialsmentioning

confidence: 99%

Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Jang

Sartor

Barata

et al. 2020

Cancers

View full text Add to dashboard Cite

Metastatic castration-resistant prostate cancer (mCRPC) is an incurable malignancy with a poor prognosis. Up to 30% of patients with mCRPC have mutations in homologous recombination repair (HRR) genes. Poly (ADP-ribose) polymerase (PARP) inhibitors take advantage of HRR deficiency to kill tumor cells based on the concept of synthetic lethality. Several PARP inhibitors (PARPis) have been successful in various malignancies with HRR gene mutations including BRCA1/2, especially in breast cancer and ovarian cancer. More recently, olaparib and rucaparib were approved for mCRPC refractory to novel hormonal therapies, and other PARPis will likely follow. This article highlights the mechanism of action of PARPis at the cellular level, the preclinical data regarding a proposed mechanism of action and the effectiveness of PARPis in cancer cell lines and animal models. The article expands on the clinical development of PARPis in mCRPC, discusses potential biomarkers that may predict successful tumor control, and summarizes present and future clinical research on PARPis in the metastatic disease landscape.

show abstract

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

Cited by 11 publications

References 49 publications

Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond

Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond

Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer

Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Contact Info

Product

Resources

About