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Updated: Feb 14, 2026
Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma
Published on: April 11, 2018
CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications
A Laroche-Clary1, C Lucchesi1, C Rey1
1INSERM ACTION U1218; Sarcoma Uni, Medical Oncology, Institute Bergonié, Bordeaux, France.
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.
Insights
Inhibiting Chk1 (Checkpoint Kinase 1) with GDC-0575 potentiates chemotherapy in soft-tissue sarcomas (STS) lacking p53. This combination shows promise, particularly in TP53-mutated STS, warranting further clinical investigation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Checkpoint Kinase 1 (Chk1) inhibition is a potential strategy to enhance chemotherapy efficacy in tumors with G1 checkpoint defects, such as those with non-functional p53.
- The p53 pathway is frequently altered in soft-tissue sarcomas (STS), either through TP53 mutations or MDM2 amplification.
- GDC-0575 is a selective, ATP-competitive inhibitor targeting Chk1.
Purpose of the Study:
- To evaluate the efficacy of combining the Chk1 inhibitor GDC-0575 with chemotherapy in various soft-tissue sarcoma models.
- To assess the impact of p53 status on the response to GDC-0575 and chemotherapy in STS.
- To investigate the preclinical and clinical activity of GDC-0575 in combination with gemcitabine for STS patients.
Main Methods:
- Systematic screening of 10 STS cell lines combining GDC-0575 with chemotherapy, assessing proliferation, cell death, and cell cycle.
- In vivo studies using TP53-mutated and wild-type patient-derived xenograft models of STS.
- Phase I clinical trial evaluating GDC-0575 plus gemcitabine in STS patients, including genetic profiling for resistance mechanisms.
Main Results:
- GDC-0575 inhibited DNA damage-induced checkpoints, increased DNA double-strand breaks, and induced apoptosis in STS cells.
- Synergistic or additive effects of GDC-0575 with gemcitabine were observed in TP53-proficient, but not TP53-deficient, sarcoma models in vitro and in vivo.
- A Phase I study showed exceptional responses in two TP53-mutated STS patients at low gemcitabine doses, while a wild-type TP53 patient showed no benefit. Secondary resistance was linked to DNA2 mutations.
Conclusions:
- Preclinical and clinical data support Chk1 inhibition as a strategy to potentiate chemotherapy in TP53-deficient STS.
- The combination therapy warrants further investigation in Phase II clinical trials for TP53-deficient STS.
- Understanding resistance mechanisms, such as DNA2 mutations, is crucial for optimizing Chk1 inhibitor-based therapies.
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