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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.
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 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 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 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 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 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
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 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 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 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