Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

Hong, David S.; Infante, Jeffrey R.; Janků, Filip; Jones, Suzanne F.; Nguyen, Ly M.; Burris, Howard A.; Naing, Aung; Bauer, Todd M.; Piha-Paul, Sarina A.; Johnson, Faye M.; Kurzrock, Razelle; Golden, Lisa; Hynes, Scott M.; Lin, Ji; Lin, Aimee Bence; Bendell, Johanna C.

doi:10.1200/jco.2015.64.5788

Cited by 135 publications

(155 citation statements)

References 16 publications

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“…Currently, novel inhibitors specific for CHK1 or with broader target specificity are tested in several clinical trials [42, 43]. In combination with gemcitabine, such compounds might prove efficacious with tolerable toxicity in patients with treatment-naïve advanced bladder cancers who are ineligible for cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Isono

Hoffmann

Pinkerneil

et al. 2017

J Exp Clin Cancer Res

122

111

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BackgroundMore effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide. We therefore explored the efficacy of the combination of gemcitabine and AZD7762, a checkpoint kinase 1/2 (CHK1/2) inhibitor, for bladder cancer.MethodsViability, clonogenicity, cell cycle distribution and apoptosis were assessed in urothelial cancer cell lines and various non-malignant urothelial cells treated with gemcitabine and AZD7762. DNA damage was assessed by γH2A.X and 53-BP1 staining and checkpoint activation was followed by Western blotting. Pharmacological inhibition of CHK1 and CHK2 was compared to downregulation of either CHK1 or CHK2 using siRNAs.ResultsCombined use of gemcitabine and AZD7762 synergistically reduced urothelial carcinoma cell viability and colony formation relative to either single treatment. Non-malignant urothelial cells were substantially less sensitive to this drug combination. Gemcitabine plus AZD7762 inhibited cell cycle progression causing cell accumulation in S-phase. Moreover, the combination induced pronounced levels of apoptosis as indicated by an increase in the fraction of sub-G1 cells, in the levels of cleaved PARP, and in caspase 3/7 activity. Mechanistic investigations showed that AZD7762 treatment inhibited the repair of gemcitabine-induced double strand breaks by interference with CHK1, since siRNA-mediated depletion of CHK1 but not of CHK2 mimicked the effects of AZD7762.ConclusionsAZD7762 enhanced sensitivity of urothelial carcinoma cells to gemcitabine by inhibiting DNA repair and disturbing checkpoints. Combining gemcitabine with CHK1 inhibition holds promise for urothelial cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0473-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Isono

Hoffmann

Pinkerneil

et al. 2017

J Exp Clin Cancer Res

122

111

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“…Two patients with a BRCA1 mutation [squamous cell cancer (SCC) of the base of the tongue and papillary serous ovarian cancer] had partial responses (28). Prexasertib, a CHK1 inhibitor, demonstrated objective responses in patients with SCC of the anus and head and neck cancer in a phase I study with multiple expansion cohorts (29). These preliminary results suggest that the newer inhibitors may be more successful than initial CHK1 inhibitors, which were only developed as chemopotentiators.…”

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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“…By inhibiting CHK1, CDC25 is activated, leading to an uncontrolled cell cycle and finally cell death [109]. Currently, two CHK1 inhibitors, LY2606368 and LY2603618, are being tested in phase I clinical trials [110, 111]. On the basis of these results, LY2606368 has been proposed for use in phase II trials for patients with squamous cell carcinoma [111].…”

Section: Combination Therapy Using Platinum-based Agents and Ddr-targmentioning

confidence: 99%

Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions

Basourakos

Aparicio

et al. 2017

CMC

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Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a “molecular landscape,” i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with ”BRCAness”, i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent–induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies.

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Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

Abstract: An LY2606368 dose of 105 mg/m(2) once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.

Cited by 135 publications

References 16 publications

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

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

Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions

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