The ATR Inhibitor AZD6738 Synergizes with Gemcitabine <i>In Vitro</i> and <i>In Vivo</i> to Induce Pancreatic Ductal Adenocarcinoma Regression

Wallez, Yann; Dunlop, Charles R.; Johnson, Timothy Isaac; Koh, Siang-Boon; Fornari, Chiara; Yates, James; Fernández, Sandra Bernaldo de Quirós; Lau, Alan; Richards, Frances M.; Jodrell, Duncan I.

doi:10.1158/1535-7163.mct-18-0010

Cited by 87 publications

(74 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lower doses (10–20 n m ) have been reported to produce an S‐phase accumulation similar to that produced with < 0.2 m m HU (Karnitz et al ., ; Matthews et al ., ). Inhibition of ATR is also shown to strongly synergise with these low doses of gemcitabine (Huntoon et al ., ; Prevo et al ., ; Wallez et al ., ), whereas we found that only higher concentrations (> 1 m m ) of HU sensitised melanoma TSs to ATR inhibition. We have shown that low concentrations of gemcitabine (down to 50 n m ) activate ATR–CHK1 signalling, consistent with the ability of ATR inhibitor to synergise with even lower doses of gemcitabine.…”

Section: Discussioncontrasting

confidence: 54%

Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine

Proctor

Stevenson

et al. 2019

Molecular Oncology

View full text Add to dashboard Cite

Drugs such as gemcitabine that increase replication stress are effective chemotherapeutics in a range of cancer settings. These drugs effectively block replication and promote DNA damage, triggering a cell cycle checkpoint response through the ATR–CHK1 pathway. Inhibiting this signalling pathway sensitises cells to killing by replication stress‐inducing drugs. Here, we investigated the effect of low‐level replication stress induced by low concentrations (> 0.2 m m ) of the reversible ribonucleotide reductase inhibitor hydroxyurea (HU), which slows S‐phase progression but has little effect on cell viability or proliferation. We demonstrate that HU effectively synergises with CHK1, but not ATR inhibition, in > 70% of melanoma and non‐small‐cell lung cancer cells assessed, resulting in apoptosis and complete loss of proliferative potential in vitro and in vivo . Normal fibroblasts and haemopoietic cells retain viability and proliferative potential following exposure to CHK1 inhibitor plus low doses of HU, but normal cells exposed to CHK1 inhibitor combined with submicromolar concentrations of gemcitabine exhibited complete loss of proliferative potential. The effects of gemcitabine on normal tissue correlate with irreversible ATR–CHK1 pathway activation, whereas low doses of HU reversibly activate CHK1 independently of ATR. The combined use of CHK1 inhibitor and subclinical HU also triggered an inflammatory response involving the recruitment of macrophages in vivo . These data indicate that combining CHK1 inhibitor with subclinical HU is superior to combination with gemcitabine, as it provides equal anticancer efficacy but with reduced normal tissue toxicity. These data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination.

show abstract

Section: Discussioncontrasting

confidence: 54%

Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine

Proctor

Stevenson

et al. 2019

Molecular Oncology

View full text Add to dashboard Cite

show abstract

“…In addition to its potential as monotherapy, BAY 1895344 is likely to be particularly efficacious in combination treatment with DNA damage-inducing or DNA repair-compromising therapies, as indicated in earlier studies (40)(41)(42)(43)(44). Here, we have demonstrated in preclinical tumor models that BAY 1895344 exhibits synergistic antitumor efficacy with EBRT in colorectal cancer, with the PARPi olaparib in PARPi-sensitive, HR-defective (BRCA1-mutant) breast cancer as well as in PARPi-resistant prostate cancer and enhanced antitumor activity in combination with the AR antagonist darolutamide in hormonedependent prostate cancer.…”

Section: A C Bmentioning

confidence: 99%

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models

Wengner

Siemeister

Lücking

et al. 2020

Molecular Cancer Therapeutics

154

133

View full text Add to dashboard Cite

The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo. Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective singleagent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.

show abstract

“…Rather, ATR activity becomes critical for the survival of Myc or Cyclin E deregulated cancers with oncogene-induced replication stress [171,172]. Specific ATR inhibitors (ATRi), such as VE-821 and AZD6738, sensitize diverse cancer cell models to genotoxic agents, including cross-linking agents, topoisomerase I or II inhibitors, PARP inhibitors and the nucleoside analog gemcitabine [173][174][175][176][177], by allowing premature mitosis with incomplete DNA replication or chromosome separation. For similar reasons, cancer cells deficient for other G2/M checkpoint regulators-ATM or TP53, are also hypersensitive to ATR inhibition [178][179][180].…”

Section: Pi3kks Inhibition Synthetic Lethality and Cancer Therapymentioning

confidence: 99%

ATM, ATR and DNA-PKcs kinases—the lessons from the mouse models: inhibition ≠ deletion

2020

View full text Add to dashboard Cite

DNA damage, especially DNA double strand breaks (DSBs) and replication stress, activates a complex post-translational network termed DNA damage response (DDR). Our review focuses on three PI3-kinase related protein kinases-ATM, ATR and DNA-PKcs, which situate at the apex of the mammalian DDR. They are recruited to and activated at the DNA damage sites by their respective sensor protein complexes-MRE11/RAD50/NBS1 for ATM, RPA/ ATRIP for ATR and KU70-KU80/86 (XRCC6/XRCC5) for DNA-PKcs. Upon activation, ATM, ATR and DNA-PKcs phosphorylate a large number of partially overlapping substrates to promote efficient and accurate DNA repair and to coordinate DNA repair with other DNA metabolic events (e.g., transcription, replication and mitosis). At the organism level, robust DDR is critical for normal development, aging, stem cell maintenance and regeneration, and physiological genomic rearrangements in lymphocytes and germ cells. In addition to endogenous damage, oncogene-induced replication stresses and genotoxic chemotherapies also activate DDR. On one hand, DDR factors suppress genomic instability to prevent malignant transformation. On the other hand, targeting DDR enhances the therapeutic effects of anti-cancer chemotherapy, which led to the development of specific kinase inhibitors for ATM, ATR and DNA-PKcs. Using mouse models expressing kinase dead ATM, ATR and DNA-PKcs, an unexpected structural function of these kinases was revealed, where the expression of catalytically inactive kinases causes more genomic instability than the loss of the proteins themselves. The spectrum of genomic instabilities and physiological consequences are unique for each kinase and depends on their activating complexes, suggesting a model in which the catalysis is coupled with DNA/chromatin release and catalytic inhibition leads to the persistence of the kinases at the DNA lesion, which in turn affects repair pathway choice and outcomes. Here we discuss the experimental evidences supporting this mode of action and their implications in the design and use of specific kinase inhibitors for ATM, ATR and DNA-PKcs for cancer therapy.

show abstract

The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression

Cited by 87 publications

References 55 publications

Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine

Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models

ATM, ATR and DNA-PKcs kinases—the lessons from the mouse models: inhibition ≠ deletion

Contact Info

Product

Resources

About