Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines

Kubota, Eiji; Williamson, Christopher T; Ye, Ruiqiong; Elegbede, A.; Peterson, Lars E.; Lees‐Miller, Susan P.; Bebb, D. Gwyn

doi:10.4161/cc.29212

Cited by 110 publications

(116 citation statements)

References 51 publications

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“…2 Following on from their studies in ATM-defective Mantle cell leukemia, 3 and similar studies in ATM-defective (11q deletion) chronic lymphocytic leukemia, 4 the group in Calgary now demonstrate the increased sensitivity of gastric carcinoma cells with low levels of ATM protein and p53 dysfunction to the PARPi, olaparib. 5 They support this finding with a number of complementary approaches using unmatched cells with differing ATM and p53 status, ATM and p53 knockdown and the use of inhibitors, with converging results. Based on these data one might speculate that PARP, by promoting repair, reduces replication stress and replication-associated DSBs and that p53 and ATM prevent replication stress leading to cell death by activating cell cycle arrest and also promoting repair.…”

Section: Please Scroll Down For Articlesupporting

confidence: 50%

PARP inhibitors target ATM+p53-defective gastric cancer

Curtin

2014

Cell Cycle

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Section: Please Scroll Down For Articlesupporting

confidence: 50%

PARP inhibitors target ATM+p53-defective gastric cancer

Curtin

2014

Cell Cycle

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“…Preclinical evaluation of olaparib in ATM-deficient leukemic cells from patients with CLL suggested single-agent activity (70). Similar findings were described in mantle cell lymphoma and gastric cancer (71,72). Furthermore, a phase II double-blind study of paclitaxel with or without olaparib for patients with gastric cancer stratified patients between low or undetectable ATM levels versus normal ATM levels.…”

Section: Parp Inhibitorsmentioning

confidence: 55%

ATM Mutations in Cancer: Therapeutic Implications

Choi¹,

Kipps²,

Kurzrock³

2016

Molecular Cancer Therapeutics

362

318

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Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states.

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“…ATM-deficient MCL cell lines are especially sensitive to PARP inhibitor olaparib, the activity of which correlates with levels of ATM in p53-deficient gastric cancer. Cell lines deficient in both ATM and p53 genes were more sensitive than cells lacking ATM function alone [184]. A phase 1 clinical trial for MCL with CEP-9722 in combination with Gemcitabine and Cisplatin has recently been completed (NCT01345357) (Table 3).…”

Section: Novel Drugs For MCL Based On Signaling Pathwaysmentioning

confidence: 99%

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

et al. 2016

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Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.

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Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines

Cited by 110 publications

References 51 publications

PARP inhibitors target ATM+p53-defective gastric cancer

PARP inhibitors target ATM+p53-defective gastric cancer

ATM Mutations in Cancer: Therapeutic Implications

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

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