CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications

Ann Oncol. 2018 Apr 1;29(4):1023-1029. doi: 10.1093/annonc/mdy039.


Background: Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1.

Methods: We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were carried out by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC-0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed.

Results: We found that GDC-0575 abrogated DNA damage-induced S and G2-M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase I study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2.

Conclusion: We provide the first preclinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase II setting.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / antagonists & inhibitors*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Gemcitabine
  • Genes, p53
  • Heterografts
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Mutation
  • Piperidines / pharmacology
  • Pyridines / pharmacology
  • Pyrroles / pharmacology
  • Soft Tissue Neoplasms / enzymology*
  • Soft Tissue Neoplasms / genetics
  • Soft Tissue Neoplasms / pathology
  • Tumor Suppressor Protein p53 / genetics


  • GDC-0575
  • Piperidines
  • Pyridines
  • Pyrroles
  • Tumor Suppressor Protein p53
  • Deoxycytidine
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Gemcitabine