Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors

Sausville, Edward A.; LoRusso, Patricia; Carducci, Michael A.; Carter, Judith; Quinn, Mary Flanagan; Malburg, Lisa; Azad, Nilofer S.; Cosgrove, David; Knight, Richard; Barker, Peter; Zabludoff, Sonya; Agbo, Felix; Oakes, Patricia; Senderowicz, Adrian M.

doi:10.1007/s00280-014-2380-5

Cited by 160 publications

(138 citation statements)

References 23 publications

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“…Second, dose-dependent toxicities are a major cause of drug attrition. Clinical development of several checkpoint kinase inhibitors has been discontinued, the most recent being AZD7762 given its untoward cardiotoxicity (35). We have shown that a threshold of CHK1 inhibition beyond that necessary for synergy is required for overt checkpoint abrogation.…”

Section: Discussionmentioning

confidence: 99%

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

et al. 2015

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Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G 2 -M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G 2 -M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S-G 2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a "foot-in-the-door" mechanism for drug synergy where cells were destroyed not by frank G 2 -M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. Cancer Res; 75(17); 3583-95. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

et al. 2015

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“…As a result of these data, clinical trials with early CHK1 inhibitors focused on the chemopotentiation of cytotoxic drugs. Although phase I trials demonstrated proof of concept that CHK1 inhibitors could be safely combined with chemotherapy (17)(18)(19)(20)(21)(22)(23)(24)(25), phase II studies failed to meet their primary endpoints (26,27). Early CHK1 inhibitors were not successful for a variety of reasons, including pharmacokinetic properties, unacceptable toxicities, and business considerations.…”

Section: Strategies For Clinical Development: Past and Presentmentioning

confidence: 99%

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin

McNeely

Beckmann

2017

Clinical Cancer Research

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All cancers are characterized by defects in the systems that ensure strict control of the cell cycle in normal tissues. The consequent excess tissue growth can be countered by drugs that halt cell division, and, indeed, the majority of chemotherapeutics developed during the last century work by disrupting processes essential for the cell cycle, particularly DNA synthesis, DNA replication, and chromatid segregation. In certain contexts, the efficacy of these classes of drugs can be impressive, but because they indiscriminately block the cell cycle of all actively dividing cells, their side effects severely constrain the dose and duration with which they can be administered, allowing both normal and malignant cells to escape complete growth arrest. Recent progress in understanding how cancers lose control of the cell cycle, coupled with comprehensive genomic profiling of human tumor biopsies, has shown that many cancers have mutations affecting various regulators and checkpoints that impinge on the core cell-cycle machinery. These defects introduce unique vulnerabilities that can be exploited by a next generation of drugs that promise improved therapeutic windows in patients whose tumors bear particular genomic aberrations, permitting increased dose intensity and efficacy. These developments, coupled with the success of new drugs targeting cell-cycle regulators, have led to a resurgence of interest in cellcycle inhibitors. This review in particular focuses on the newer strategies that may facilitate better therapeutic targeting of drugs that inhibit the various components that safeguard the fidelity of the fundamental processes of DNA replication and repair. Clin Cancer Res; 23(13); 3232-40. Ó2017 AACR.

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“…Several CHK1 inhibitors have been advanced to clinical trial [15][16][17][18] and like other targeted agents their development requires pharmacodynamic biomarkers to verify target inhibition and subsequent modulation of appropriate molecular pathways in vivo. One of the most widely used markers to confirm the biological activity of CHK1 inhibitors in experimental systems has been phosphorylation of histone H3 at Ser10, which normally occurs in cells entering mitosis and is therefore indicative of either passage through the G2 checkpoint or direct entry of S-phase arrested cells into mitosis (termed premature mitosis).…”

Section: Introductionmentioning

confidence: 99%

Dissociation of gemcitabine chemosensitization by CHK1 inhibition from cell cycle checkpoint abrogation and aberrant mitotic entry

et al. 2016

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In order to determine the relative contribution of checkpoint abrogation and subsequent aberrant mitotic entry to gemcitabine chemosensitization by CHK1 inhibition, we established a model utilizing the CDK inhibitors roscovitine or purvalanol A to re-establish cell cycle arrest and prevent aberrant mitotic entry in pancreatic cancer cells treated with gemcitabine and the CHK inhibitor AZD7762. In this study, we report that the extent of aberrant mitotic entry, as determined by flow cytometry for the mitotic marker phospho-Histone H3 (Ser10), did not reflect the relative sensitivities of pancreatic cancer cell lines to gemcitabine chemosensitization by AZD7762. In addition, re-establishing gemcitabine-induced cell cycle arrest either pharmacologically, with roscovitine or purvalanol A, or genetically, with cyclin B1 siRNA, did not inhibit chemosensitization uniformly across the cell lines. Furthermore, we found that AZD7762 augmented high-intensity gH2AX signaling in gemcitabine-treated cells, suggesting the presence of replication stress when CHK1 is inhibited. Finally, the ability of roscovitine to prevent chemosensitization correlated with its ability to inhibit AZD7762-induced high-intensity gH2AX, but not aberrant pHH3, suggesting that the effects of AZD7762 on DNA replication or repair rather than aberrant mitotic entry determine gemcitabine chemosensitization in pancreatic cancer cells.

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Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors

Cited by 160 publications

References 23 publications

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Dissociation of gemcitabine chemosensitization by CHK1 inhibition from cell cycle checkpoint abrogation and aberrant mitotic entry

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