Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

Borst, Gerben R.; McLaughlin, Martin; Kyula, Joan; Neijenhuis, Sari; Khan, Aadil; Good, James; Zaidi, Shane; Powell, Ned; Meier, Pascal; Collins, Ian; Garrett, Michelle D.; Verheij, Marcel; Harrington, Kevin

doi:10.1016/j.ijrobp.2012.08.006

Cited by 46 publications

(38 citation statements)

References 17 publications

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“…1A). We, and others, have previously shown that phospho-S345 CHK1 is the most consistent pharmacodynamic biomarker of CHK1 inhibition (16,17). Western blot analysis confirmed CCT244747 drug-ontarget activity as demonstrated by increased p-CHK1 expression (Fig.…”

Section: Chk1 Inhibition Radiosensitizes Hn4 and Hn5 Cellssupporting

confidence: 59%

CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy

Barker

Patel

McLaughlin

et al. 2016

Molecular Cancer Therapeutics

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Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitizer and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G 2 arrest in the p53-deficient HNSCC cell lines HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV þ patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. Ó2016 AACR.

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Section: Chk1 Inhibition Radiosensitizes Hn4 and Hn5 Cellssupporting

confidence: 59%

CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy

Barker

Patel

McLaughlin

et al. 2016

Molecular Cancer Therapeutics

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“…Since then other Chk1 inhibitors have been studied for their radiosensitizing properties. The Chk1 inhibitors SAR-02106 and AZD7762 have been shown in pre-clinical studies to radiosensitize p53-deficient tumor cells in culture and human tumor xenografts made using p53-defective cells [21, 22]. Two additional Chk1 inhibitors, XL-844 and PF-00477736, are also capable of radiosensitization [23, 24].…”

Section: Introductionmentioning

confidence: 99%

MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells

et al. 2016

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Radiotherapy is commonly used to treat a variety of solid tumors but improvements in the therapeutic ratio are sorely needed. The aim of this study was to assess the Chk1 kinase inhibitor, MK-8776, for its ability to radiosensitize human tumor cells. Cells derived from NSCLC and HNSCC cancers were tested for radiosensitization by MK-8776. The ability of MK-8776 to abrogate the radiation-induced G2 block was determined using flow cytometry. Effects on repair of radiation-induced DNA double strand breaks (DSBs) were determined on the basis of rad51, γ-H2AX and 53BP1 foci. Clonogenic survival analyses indicated that MK-8776 radiosensitized p53-defective tumor cells but not lines with wild-type p53. Abrogation of the G2 block was evident in both p53-defective cells and p53 wild-type lines indicating no correlation with radiosensitization. However, only p53-defective cells entered mitosis harboring unrepaired DSBs. MK-8776 appeared to inhibit repair of radiation-induced DSBs at early times after irradiation. A comparison of MK-8776 to the wee1 inhibitor, MK-1775, suggested both similarities and differences in their activities. In conclusion, MK-8776 radiosensitizes tumor cells by mechanisms that include abrogation of the G2 block and inhibition of DSB repair. Our findings support the clinical evaluation of MK-8776 in combination with radiation.

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“…Thus, the concept of targeting CHK1 in tumors harboring deficient p53 for selective sensitization to radiation or to chemotherapeutic agents has been validated over the last decade using numerous CHK1 inhibitors (23)(24)(25)(26)(27)(28)47). Inhibition of CHK1 in various cancer types harboring p53 mutation including breast cancer, multiple myeloma, colon carcinoma, pancreatic cancer, and brain glioblastoma resulted in cell death mainly via mitotic catastrophe when simultaneously exposed to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of the phenomenon of synthetic lethality, targeting CHK1 therefore represents a promising concept to sensitize tumors to cytotoxic agents in case of compromised p53 activity (17). Several potent CHK1 inhibitors such as AZD7762, CHIR-124, or SAR-020106 have been reported to enhance the cytotoxicity of DNA-damaging agents in p53-defective tumor cells by the abrogation of the cell-cycle arrest and premature entry into mitosis (23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition–Associated Checkpoint Abrogation

Mikami

Medová

Nisa

et al. 2015

Molecular Cancer Research

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Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G 2 -M cell-cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G 1 -S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G 1 -S and G 2 -M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wild-type p53 lines as inferred from elevated gH2AX expression and increased cytotoxicity. Furthermore, cell-cycle distribution profiling indicates constantly lower G 1 and higher G 2 -M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared with the parental counterpart.Implications: The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, as p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA-damaging agents for MET-positive/p53-negative tumors.

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Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

Cited by 46 publications

References 17 publications

CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy

CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy

MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells

Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition–Associated Checkpoint Abrogation

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