Reference Detail

Ref Type

Journal Article

PMID

(29409053)

Authors

Laroche-Clary A, Lucchesi C, Rey C, Verbeke S, Bourdon A, Chaire V, Algéo MP, Cousin S, Toulmonde M, Vélasco V, Shutzman J, Savina A, Le Loarer F, Italiano A

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology	29	4	2018 Apr 01	1023-1029	Ann Oncol

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 mutant	fibrous histiocytoma	predicted - sensitive	GDC-0575 + Gemcitabine	Preclinical - Pdx	Actionable	In a preclinical study, GDC-0575 and Gemzar (gemcitabine) combination treatment inhibited tumor growth, prolonged progression-free survival in patient-derived xenogrft (PDX) models of undifferentiated pleomorphic sarcoma (fibrous histiocytoma) (PMID: 29409053).	29409053
TP53 mutant	sarcoma	predicted - sensitive	GDC-0575 + Gemcitabine	Phase I	Actionable	In a Phase I trial, GDC-0575 and Gemzar (gemcitabine) combination treatment resulted in a prolonged tumor response in 2 soft tissue sarcoma patients harboring TP53 mutations, and no response in a patient with TP53 wild-type tumor (PMID: 29409053; NCT01564251).	29409053