Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

Calvo, Emiliano; Braiteh, Fadi; Hoff, Daniel D. Von; McWilliams, Robert R.; Becerra, Carlos; Galsky, Matthew D.; Jameson, Gayle; Lin, Ji; McKane, Scott; Wickremsinhe, Enaksha; Hynes, Scott M.; Lin, Aimee Bence; Hurt, Karla; Richards, Donald A.

doi:10.1159/000448621

Cited by 36 publications

(32 citation statements)

References 17 publications

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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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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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“…As expected, this combined treatment inhibits colony formation (4), increases clonogenic cell death (6) and inhibits tumor growth compared with GEM treatment alone (7)(8)(9)(10). Phase I clinical trials have been initiated, and the recommended phase II dose has been shown (11)(12)(13)(14)(15). However, concerns about unpredicted effects of Chk1 inhibitors on normal cells have been raised (12,16).…”

Section: Introductionmentioning

confidence: 89%

Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells

et al. 2017

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Abstract. Although gemcitabine (GEM) is frequently used in the treatment of pancreatic cancer, the effects are limited. To increase the inhibitory effect of GEM, the identification of a molecular target is needed. Recent studies have revealed that doublecortin-like kinase 1 (Dclk1) positively regulates tumor growth, invasion, metastasis, factors related to epithelialmesenchymal transition (EMT), pluripotency, angiogenesis, and anti-apoptosis in pancreatic cancer cells. Therefore, Dclk1 is a potential therapeutic target for pancreatic cancer. However, the Dclk1-signaling pathway including its substrate proteins remains to be elucidated. To identify the candidate substrate proteins phosphorylated by Dclk1, we performed a cancer-related phosphorylated protein microarray using Dclk1-inhibited MIA Paca2 cells. Expression levels of phosphorylated cdc25A (p-cdc25A) and phosphorylated Chk1 (p-Chk1), belonging to the ATR pathway, were decreased by treatment with Dclk1 inhibitor LRRK2-IN-1 (LRRK), indicating Dclk1 involvement in the ATR pathway. Consistent with this finding, the GEM-induced p-Chk1 expression was significantly decreased by treatment with LRRK. Notably, combined treatment with GEM and LRRK allowed cell cycle progression without arresting at S phase, while individual treatment with GEM induced cell cycle arrest at S phase. In addition, combined treatment with GEM and LRRK increased the number of γ-H2AX-positive cells compared with that upon individual treatments. Moreover, LRRK alone, and combined treatment with GEM and LRRK, induced caspase-3 activation and PARP1 cleavage, in contrast to treatment with GEM alone. Finally, combined treatment with GEM and LRRK significantly reduced cell survival compared to individual treatment with GEM. These results indicate that Dclk1 inhibition in combination with GEM treatment offers a novel approach to treat pancreatic cancer cells.

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“…Most of the CHK1i clinical trials have been in combination with gemcitabine, the standard-of-care drug in many cancer types, which is usually used in maximum tolerated dose (MTD) when combined with CHK1i and potentially resulted in enhanced normal tissue toxicity as reported in previous clinical trials (Calvo et al, 2016, Infante et al, 2016, Sausville et al, 2014, Doi et al, 2015. Utilising low-dose HU would be more clinically feasible since HU is not standard-of-care but approved drug in many cancer types and would probably result in less toxicity to normal tissue.…”

Section: Discussionmentioning

confidence: 99%

“…CHK1 inhibitors have been investigated in preclinical studies and clinical trials in combination with chemotherapeutic agents. Despite the initial hope it offered, CHK1 inhibitor in combination with chemotherapeutic drugs have shown varying efficacies in patients (Seto et al, 2013, Sausville et al, 2014, Calvo et al, 2016, Doi et al, 2015. More specific CHK1 inhibitors were developed along the way and their efficacy to enhance chemotherapy were also being evaluated and reported to be more successful than the previous attempts.…”

Section: Discussionmentioning

confidence: 99%

“…CHK1i monotherapy treatment to have well-tolerated toxicity (Daud et al, 2015, Infante et al, 2016, while CHK1i combination with gemcitabine treatment group had more adverse side-effects possibly due to the combining adverse effects of CHK1i inhibition with the standard dosage of gemcitabine (800-1000 mg/m 2 ) (Calvo et al, 2016, Sausville et al, 2014, Doi et al, 2015. Since…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms and markers of CHK1 inhibitors sensitivity in melanoma

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Landscape for the treatment of cancer patients has recently been changed with the arrival of targeted therapies in different malignancies with the drugs targeting specific mutations and genetic alterations such as, EGF-receptor blockers and BRAF inhibitors, and the drugs such as PARP inhibitors which exploit defects in the cancers and cause synthetic lethality. In this thesis, I investigated to understand the mechanism of action of a drug that targets the cell cycle checkpoint regulator, checkpoint kinase 1 (CHK1) and explored its potential therapeutic usage in specific cancer types. Checkpoint kinase 1 inhibitor (CHK1i) as a single-agent treatment is effective in some of the cancer types with high levels of replication stress, including melanoma. However, the mechanism and manner of cell-killings induced by CHK1i single-agent treatment is still poorly understood. To identify the patient population who can benefit from CHK1i single-agent treatment, it is important to understand how single-agent CHK1i induced the cell killing. CHK1i has been investigated in pre-clinical studies and clinical trials, and shown to enhance the efficacy of chemotherapeutic drugs, particularly those that promote replication stress such as gemcitabine.Most of those investigations were based on the previous notion that CHK1i abrogates the G2/M phase checkpoint to cause mitotic catastrophe and results in cancer cell death. However, considering numerous roles of CHK1 playing in cell cycle and DNA damage response pathway, this mechanism alone may not represent the entirety of sensitivity to CHK1i. CHK1 has different roles in S and G2/M phases of cell cycle such as controlling the G2/M checkpoint, stabilising the stalled replication fork, and inhibiting the apoptosis together with other DNA damage repair and cell cycle checkpoint regulators. When one of these other regulators/pathways has defects, inhibiting CHK1 can be synthetically lethal to the cancer cells. Another CHK1 function in S phase is regulating CDC25A; CHK1 triggers the destabilisation of CDC25A upon DNA damage and replication stress.The normal role of CDC25A in S phase progression is activation of CDK2 which is required for progression into and through S phase. CDC25A dysregulation and overexpression has been reported in various cancers and shown to create increased replication stress in the cells. Tumours with high level of replication stress have been suggested to be selectively susceptible to the inhibition of CHK1 and its upstream regulator, ATR.In this thesis, it was firstly shown that S phase cell cycle checkpoint defect is a common feature of CHK1i-hypersensitive melanoma cell lines, and this defect is often associated with failure to degrade CDC25A in response to replication stress. Furthermore, CDC25A over-expression and/or dysregulation contributes to CHK1i sensitivity in hypersensitive melanoma cell lines. Secondly, it was demonstrated that CHK1i induced high level of replication stress via RPA hyperphosphorylation and subsequently RPA depletion occurred in h...

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Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

Cited by 36 publications

References 17 publications

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

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

Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells

Mechanisms and markers of CHK1 inhibitors sensitivity in melanoma

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