Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress

Thomas, Anish; Takahashi, Nobuyuki; Rajapakse, Vinodh N.; Zhang, Xiaohu; Sun, Yilun; Ceribelli, Michele; Wilson, Kelli; Zhang, Yang; Beck, Erin; Sciuto, Linda; Nichols, Samantha; Elenbaas, Brian; Puc, Janusz; Dahmen, Heike; Zimmermann, Astrid; Varonin, Jillian; Schultz, Christopher W.; Kim, Se Hyun; Shimellis, Hirity; Desai, Parth; Klumpp‐Thomas, Carleen; Chen, Lu; Travers, Jameson; McKnight, Crystal; Michael, Sam; Itkin, Zina; Lee, Sunmin; Yuno, Akira; Redon, Christophe E.; Kindrick, Jessica; Peer, Cody J.; Wei, Jun S.; Aladjem, Mirit I.; Figg, William D.; Steinberg, Seth M.; Trepel, Jane B.; Zenke, Frank T.; Pommier, ﻿Yves; Khan, Javed; Thomas, Craig J.

doi:10.1016/j.ccell.2021.02.014

Cited by 126 publications

(132 citation statements)

References 76 publications

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“… 23 A subsequent proof-of-concept Phase 2 study with berzosertib in combination with topotecan in patients with SCLC reported an objective response rate of 36% (9/25), with a median duration of response of 6.4 months, including those with platinum-resistant disease unlikely to respond to topotecan alone. 24 Furthermore, in a randomised Phase 2 study, patients with platinum-resistant HGSOC, especially those who had a platinum-free interval <3 months, experienced longer PFS following treatment with berzosertib in combination with gemcitabine compared to gemcitabine alone. 25 Taken together, these results may suggest that berzosertib, likely in combination with a synergistic chemotherapeutic drug, such as gemcitabine, a topoisomerase inhibitor or platinum compounds, may be clinically active in tumours under replicative stress, such as SCLC or HGSOC, and may potentially help overcome platinum and/or PARP inhibitor resistance.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours

et al. 2021

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Background Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin. Methods Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W). Results Thirty-one patients received berzosertib (90–210 mg/m2) and cisplatin (40–75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy. Conclusions Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting. Clinical Trials Identifier NCT02157792.

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Section: Discussionmentioning

confidence: 99%

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours

et al. 2021

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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%

“…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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“…Our study suggests that the inhibition of the ATR-CHK1 pathway might be therapeutically exploited in CALR mutated MPNs. Multiple CHK1 inhibitors and ATR inhibitors are at different stages of clinical development in several malignancies [ 45 – 47 ]. Exploring such inhibitors in CALR mutated MPNs would significantly shorten the time required to make a new therapeutic modality available to MPN patients who currently have a limited repertoire of treatment options.…”

Section: Discussionmentioning

confidence: 99%

High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells

et al. 2021

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Mutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia and primary myelofibrosis. To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we searched for small molecules that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89 172 compounds using isogenic cell lines carrying CALR mutations and identified synthetic lethality with compounds targeting the ATR-CHK1 pathway. The selective inhibitory effect of these compounds was validated in a co-culture assay of CALR mutated and wild-type cells. Of the tested compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing wild-type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to ATR-CHK1 inhibition, thus suggesting specificity for the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. This was accompanied by S-phase cell cycle arrest due to incomplete DNA replication. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by oncogenic CALR, suggesting an intrinsic vulnerability to CHK1 perturbation. This study reveals the ATR-CHK1 pathway as a potential therapeutic target in CALR mutated hematopoietic cells.

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Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress

Cited by 126 publications

References 76 publications

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours

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

High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells

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