Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study

Yap, Timothy A.; Krebs, Matthew; Postel-Vinay, Sophie; El-Khoueiry, Anthony B.; Soria, Jean‐Charles; Lopez, Juanita; Berges, Aliénor; Cheung, Sy Amy; Irurzun-Arana, Itziar; Goldwin, Andrew; Felicetti, B.; Jones, Gemma N.; Lau, Alan; Frewer, Paul; Pierce, Andrew J.; Clack, Glen; Stephens, C.; Smith, Simon A.; Dean, Emma; Hollingsworth, Simon J.

doi:10.1158/1078-0432.ccr-21-1032

Cited by 60 publications

(63 citation statements)

References 26 publications

(41 reference statements)

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“…Enhancing replicative damage by blunting the RepStress response pathways with ATR inhibitors is discussed below [8,[63][64][65][66][67]. Synthetic lethality for the PARP inhibitors and platinum derivatives in HRD cancers is being applied for cancer treatment [68,69] and recent studies in animal models suggest such synthetic lethality for TOP1 inhibitors [10,58].…”

Section: Repstress Induced By Clinically Approved Chemotherapeutic Agentsmentioning

confidence: 99%

“…Three ATR inhibitors are in advanced clinical development: Berzosertib (M6620, alias VX-970), Ceralasertib (AZD6738), and Elimusertib (BAY1895344) [8,[65][66][67]108]. Additional drugs are in early development comprising M4344 and M1774 (EMD-Serono Merck, Darmstadt, Germany), ART0380 (Artios Pharma, New York, NY, USA) and RP-3500 (Repare Therapeutics, Quebec, QC, Canada) [64].…”

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

“…Currently, over 30 clinical trials are ongoing with ATR inhibitors alone or in combination with DNA damaging agents including nucleoside analogues, platinumbased agents, TOP and PARP inhibitors [5,6,63,64,66,[109][110][111]. Broadly, these clinical trials aim to exploit: (i) the synthetic lethal interactions of the ATR-CHK1 pathway with the overexpression of oncogenes (RAS, APOBEC3A, and c-MYC), deficiency of ATM and ARID1A (AT-rich interaction domain 1A) and SLFN11 [6,63,65,85,92] using ATR inhibitor monotherapy or (ii) the dependence of high RepStress tumors on ATR, generally in combination with RepStress-inducing agents (described in Sections 3.4 and 3.5).…”

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

“…The differential pharmacokinetics of ATR inhibitors is another important consideration. Although their plasma elimination half-life are comparable (approximately 12 h) [65][66][67]108], serum protein binding and thus free drug availability, tumor penetration/retention, and blood-brain barrier penetration may be different.…”

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

“…Although quiescent normal cells are likely to be spared by ATR inhibitors, effects on replicating cells will be dose-limiting. This practical challenge is being addressed by adjusting doses and schedules in the combinations of ATR inhibitors and DNA-targeted chemotherapies [8,65,66]. Another approach being explored in our NCI clinic is to combine ATR inhibitors with tumor-targeted DNA damaging agents, such as tumor-targeted TOP1 inhibitors (TTT is).…”

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

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Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Murai

Takebe

et al. 2021

Cancers

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Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.

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Section: Repstress Induced By Clinically Approved Chemotherapeutic Agentsmentioning

confidence: 99%

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Targeting the Repstress Response With Replication Checkpoint Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Murai

Takebe

et al. 2021

Cancers

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Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Zhao

Li²,

Wang

et al. 2023

Cancer Medicine

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Background Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by the untargetable non‐G12C KRAS mutations, and only a small subset of patients are eligible for FDA‐approved precision therapies. The practice of precision therapy in pancreatic cancer was limited by the paucity of targetable genetic alterations, especially in the Asian population. Methods To explore therapeutic targets in 499 Chinese PDAC patients, a deep sequencing panel (OncoPanscan™, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants. Results We performed genomic profiling in 499 Chinese PDAC patients, which revealed somatic driver mutations in KRAS, TP53, CDKN2A, SMAD4, ARID1A, RNF43, and pathogenic germline variants (PGVs) in cancer predisposition genes including BRCA2, PALB2, and ATM. Overall, 20.4% of patients had targetable genomic alterations. About 8.4% of patients carried inactivating germline and somatic variants in BRCA1/2 and PALB2, which were susceptible to platinum and PARP inhibitors therapy. Patients with KRAS wild‐type disease and early‐onset pancreatic cancer (EOPC) harbored actionable mutations including BRAF, EGFR, ERBB2, and MAP2K1/2. Compared to PGV‐negative patients, PGV‐positive patients were younger and more likely to have a family history of cancer. Furthermore, PGVs in PALB2, BRCA2, and ATM were associated with high PDAC risk in the Chinese population. Conclusions Our results demonstrated that a genetic screen of actionable genomic variants could facilitate precision therapy and cancer risk reduction in pancreatic cancer patients of Asian ethnicity.

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Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma

Ura,

Hayashi,

Komura

et al. 2023

The Journal of Pathology CR

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A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine‐specific demethylase 5D (KDM5D) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia‐telangiectasia and Rad3‐related (ATR) inhibitor treatment. We evaluated KDM5D copy number loss in 173 surgically resected SCCs from male patients using fluorescence in situ hybridization. KDM5D copy number loss was detected in 75 of the 173 patients (43%). Genome‐wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the KDM5D copy number loss are associated with ‘cell cycle’, whereas downregulated genes in tumors with KDM5D copy number loss were associated with ‘immune response’. Clinicopathologically, SCCs with KDM5D copy number loss were associated with late pathological stage (p = 0.0085) and high stromal content (p = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor‐infiltrating CD8+/T‐bet+ T cells was lower in SCCs with KDM5D copy number loss than in wild‐type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited KDM5D copy number loss. Tumors in patients who show this distinct phenotype can be ‘cold tumors’, which are characterized by the paucity of tumor T‐cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors.

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Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study

Cited by 60 publications

References 26 publications

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma

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