Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1152540 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR30399991.fastq.gz | Fastqsanger.gz |
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Project description:WEE1 inhibition triggers GCN2-mediated activation of the integrated stress response.
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Project description:WEE1 inhibition triggers GCN2-mediated activation of the integrated stress response
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Project description:Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a greater dependency of these cells on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here we conducted CRISPR/Cas9 knockout screens to identify genes influencing the response of SCLC cells to WEE1 kinase inhibition. These screens uncovered a role for the GCN2 amino acid-sensing pathway in modulating the response of SCLC cells to WEE1 inhibition. Rapid activation of GCN2 upon WEE1 inhibition triggers a stress response. Pharmacological activation of the GCN2 pathway synergizes with WEE1 inhibition. Thus, activation of the GCN2 amino acid-sensing pathway represents a novel approach for augmenting the efficacy of WEE1 inhibitors in SCLC.
2024-07-16 | GSE246354 | GEO
Project description:The WEE1 kinase negatively regulates CDK1/2 to control DNA replication and mitotic entry. Genetic factors that determine sensitivity to WEE1 inhibition (WEE1i) are largely unknown. A genome-wide insertional mutagenesis screen revealed that mutation of the alternative translation initiation factor EIF2A sensitized to WEE1i. Mechanistically, WEE1i triggers a translational shut-down, which is lethal in combination with the reduced translation of EIF2AKO cells. A genome-wide CRISPR-Cas9 screen revealed that inactivation of integrated stress response (ISR) kinases GCN1/2 rescued WEE1i-mediated cytotoxicity. Accordingly, WEE1i induced GCN2 activation, ATF4 upregulation, and altered ribosome dynamics. Accordingly, loss of the collided ribosome sensor ZNF598 increased sensitivity to WEE1i. Notably, the ISR was not required for WEE1i to induce DNA damage, premature mitotic entry nor sensitization to DNA-damaging chemotherapeutics. Conversely, ISR activation was independent of CDK1/2 activation. WEE1i-mediated ISR activation was independent of WEE1 presence, pointing at off-target effects, which are shared by multiple chemically distinct WEE1 inhibitors. This response was also observed in peripheral blood monocytic cells. Importantly, WEE1 inhibition at doses that do not induce ISR activation still synergized with PKMYT1 inhibition. Taken together, WEE1i triggers cytotoxic ISR activation and translational shutdown, which can be prevented by low-dose treatments, while retaining the cell cycle checkpoint-perturbing effects.
2025-10-07 | GSE291445 | GEO
Project description:The WEE1 kinase negatively regulates the CDK1/2 kinases to control DNA replication and prevent premature entry into mitosis. Pharmacological inhibition of WEE1 (WEE1i) causes hyperactivation of CDK1 and CDK2, leading to premature mitosis in the presence of DNA lesions. WEE1i treatment is particularly cytotoxic in cells with oncogene-induced or treatment-induced replication stress. To uncover genetic factors that sensitize cancer cells to WEE1i, a genome-wide insertional mutagenesis screen was performed and identified that mutation of the alternative translation initiation factor EIF2A sensitized cells to WEE1i. WEE1i sensitivity of EIF2AKO cells was not explained by altered replication kinetics. Rather, WEE1i leads to a translational shut-down which is lethal in combination with the reduced translation in EIF2AKO cells. A genome-wide CRISPR-Cas9 screen in WEE1i-treated cells revealed that inactivation of the integrated stress response (ISR) kinase GCN2 rescued WEE1i-mediated cytotoxicity. In line with these findings, WEE1i resulted in GCN2 activation, ATF4 upregulation and a translational shutdown. Moreover, WEE1 inhibition leads to altered ribosome dynamics and increased ribosome collisions. Accordingly, cells lacking the collided ribosome sensor ZNF598 show increased sensitivity to WEE1i. This response was not restricted to cancer cells, but was also observed in peripheral blood monocytic cells. The GCN2-mediated ISR was not required for WEE1i to induce DNA damage in S-phase, premature mitotic entry nor the sensitizing effects to DNA damaging chemotherapeutics. Conversely, ISR activation and translational shut-down are independent on WEE1i-mediated activation of CDK1/2. WEE1i-mediated ISR activation was independent of the presence of WEE1, pointing at an off-target effect, which is shared by multiple chemically distinct WEE1 inhibitors. Importantly, WEE1 inhibition at doses that do not induce the ISR can still synergize with PKMYT1 inhibition. Taken together, pharmacological WEE1 inhibition triggers cytotoxic ISR activation and translational shutdown, which can be prevented by low-dose treatments, while retaining the cell cycle checkpoint-perturbing effects.
2025-10-05 | GSE291029 | GEO
Project description:The WEE1 kinase negatively regulates the CDK1/2 kinases to control DNA replication and prevent premature entry into mitosis. Pharmacological inhibition of WEE1 (WEE1i) causes hyperactivation of CDK1 and CDK2, leading to premature mitosis in the presence of DNA lesions. WEE1i treatment is particularly cytotoxic in cells with oncogene-induced or treatment-induced replication stress. To uncover genetic factors that sensitize cancer cells to WEE1i, a genome-wide insertional mutagenesis screen was performed and identified that mutation of the alternative translation initiation factor EIF2A sensitized cells to WEE1i. WEE1i sensitivity of EIF2AKO cells was not explained by altered replication kinetics. Rather, WEE1i leads to a translational shut-down which is lethal in combination with the reduced translation in EIF2AKO cells. A genome-wide CRISPR-Cas9 screen in WEE1i-treated cells revealed that inactivation of the integrated stress response (ISR) kinase GCN2 rescued WEE1i-mediated cytotoxicity. In line with these findings, WEE1i resulted in GCN2 activation, ATF4 upregulation and a translational shutdown. Moreover, WEE1 inhibition leads to altered ribosome dynamics and increased ribosome collisions. Accordingly, cells lacking the collided ribosome sensor ZNF598 show increased sensitivity to WEE1i. This response was not restricted to cancer cells, but was also observed in peripheral blood monocytic cells. The GCN2-mediated ISR was not required for WEE1i to induce DNA damage in S-phase, premature mitotic entry nor the sensitizing effects to DNA damaging chemotherapeutics. Conversely, ISR activation and translational shut-down are independent on WEE1i-mediated activation of CDK1/2. WEE1i-mediated ISR activation was independent of the presence of WEE1, pointing at an off-target effect, which is shared by multiple chemically distinct WEE1 inhibitors. Importantly, WEE1 inhibition at doses that do not induce the ISR can still synergize with PKMYT1 inhibition. Taken together, pharmacological WEE1 inhibition triggers cytotoxic ISR activation and translational shutdown, which can be prevented by low-dose treatments, while retaining the cell cycle checkpoint-perturbing effects.
2025-10-05 | GSE287601 | GEO
Project description:WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response.
| PRJNA1233770 | ENA
Project description:we demonstrate that the WEE1 inhibitor AZD1775 triggers endoplasmic reticulum (ER) stress and activates the PERK and IRE1α branches of the unfolded protein response (UPR) in TP53 mutant HGSOC cells. Upon AZD1775 treatment, PERK facilitates apoptotic signaling in these cells via activating CHOP, whereas IRE1α-induced spliced XBP1 (XBP1s) confers survival in response to WEE1 inhibition. Our data uncover an important dual role of UPR in TP53 mutant HGSOC cells in response to AZD1775, where additional inhibition of IRE1α-XBP1s signaling may offer synergistic efficacy.
2021-02-10 | GSE166417 | GEO
Project description:Cancers invoke various pathways to mitigate external and internal stresses to continue their growth and progression. We previously reported that the eIF2 kinase GCN2 and the integrated stress response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, although loss of GCN2 function reduces intracellular amino acid availability and PCa growth, there is no appreciable cell death. Here, we discovered that the loss of GCN2 in PCa induces prosenescent p53 signaling. This p53 activation occurred through GCN2 inhibition-dependent reductions in purine nucleotides that impaired ribosome biogenesis and, consequently, induced the impaired ribosome biogenesis checkpoint. p53 signaling induced cell cycle arrest and senescence that promoted the survival of GCN2-deficient PCa cells. Depletion of GCN2 combined with loss of p53 or pharmacological inhibition of de novo purine biosynthesis reduced proliferation and enhanced cell death in PCa cell lines, organoids, and xenograft models. Our findings highlight the coordinated interplay between GCN2 and p53 regulation during nutrient stress and provide insight into how they could be targeted in developing new therapeutic strategies for PCa.
2024-10-01 | GSE260934 | GEO