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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 | 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 | 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 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 | 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 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 |