Reference Detail

Ref Type

Journal Article

PMID

(38032106)

Authors

O'Brien S, Ubhi T, Wolf L, Gandhi K, Lin S, Chaudary N, Dhani NC, Milosevic M, Brown GW, Angers S

Title

FBXW7-loss sensitizes cells to ATR inhibition through induced mitotic catastrophe.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research communications			2023 Nov 30		Cancer Res Commun

URL

Abstract Text

FBXW7 is a commonly mutated tumor suppressor gene that functions to regulate numerous oncogenes involved in cell cycle regulation. Genome-wide CRISPR fitness screens identified a signature of DNA repair and DNA damage response genes as required for the growth of FBXW7-knockout cells. Guided by these findings, we show that FBXW7 mutant cells have high levels of replication stress, which results in a genotype-specific vulnerability to inhibition of the ATR signaling pathway, as these mutant cells become heavily reliant on a robust S-G2 checkpoint. ATR-inhibition induces an accelerated S-phase, leading to mitotic catastrophe and cell death caused by the high replication stress present in FBXW7-/- cells. In addition, we provide evidence in cell and organoid studies, and mining of publicly available high throughput drug screening efforts, that this genotype-specific vulnerability extends to multiple types of cancer, providing a rational means of identifying responsive patients for targeted therapy.

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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
FBXW7 del	cervical cancer	sensitive	Ceralasertib	Preclinical - Cell culture	Actionable	In a preclinical study, an organoid cell line generated from patient-derived xenograft tissue of cervical cancer with knockout of FBXW7 demonstrated increased sensitivity to Ceralasertib (AZD6738) treatment compared to the parental organoid cell line with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 R465H	cervical cancer	sensitive	Adavosertib	Preclinical - Cell culture	Actionable	In a preclinical study, a cervical cancer cell line harboring FBXW7 R465H demonstrated increased sensitivity to Adavosertib (MK-1775) treatment compared to a cell line with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 R465H	cervical cancer	sensitive	RP-6306	Preclinical - Cell culture	Actionable	In a preclinical study, a cervical cancer cell line harboring FBXW7 R465H demonstrated increased sensitivity to RP-6306 treatment compared to a cell line with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 del	Advanced Solid Tumor	sensitive	RP-6306	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line with knockout of FBXW7 demonstrated increased sensitivity to RP-6306 treatment compared to cells with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 del	Advanced Solid Tumor	sensitive	AZD7762	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line with knockout of FBXW7 demonstrated increased sensitivity to AZD7762 treatment compared to cells with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 R465H	cervical cancer	sensitive	Ceralasertib	Preclinical - Cell culture	Actionable	In a preclinical study, a cervical cancer cell line harboring FBXW7 R465H demonstrated increased sensitivity to Ceralasertib (AZD6738) treatment compared to cell lines with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 del	Advanced Solid Tumor	sensitive	Ceralasertib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line with knockout of FBXW7 demonstrated increased sensitivity to Ceralasertib (AZD6738) treatment compared to cells with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 del	Advanced Solid Tumor	sensitive	Adavosertib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line with knockout of FBXW7 demonstrated increased sensitivity to Adavosertib (MK-1775) compared to cells with wild-type FBXW7 in culture (PMID: 38032106).	38032106
FBXW7 R465H	cervical cancer	sensitive	AZD7762	Preclinical - Cell culture	Actionable	In a preclinical study, a cervical cancer cell line harboring FBXW7 R465H demonstrated increased sensitivity to AZD7762 treatment compared to a cell line with wild-type FBXW7 in culture (PMID: 38032106).	38032106