Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy

Cancer Research, Год журнала: 2023, Номер 83(24), С. 4095 - 4111

Опубликована: Сен. 20, 2023

Abstract Non–small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy the G12Cis adagrasib (MRTX-849) or plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant lines. Recurrent, potentially targetable, synthetic lethal (SL) were identified, including serine–threonine kinases, tRNA-modifying proteoglycan synthesis enzymes, YAP/TAZ/TEAD pathway components. Several SL confirmed by siRNA/shRNA experiments, was extensively validated in vitro mice. Mechanistic studies showed that G12Ci treatment induced gene expression RHO paralogs activators, increased RHOA activation, evoked ROCK-dependent nuclear translocation YAP. Mice patients acquired G12Ci- G12Ci/SHP2i-resistant tumors strong overlap pathways, arguing for relevance screen results. These findings provide landscape potential targets future combination strategies, some can be tested rapidly clinic. Significance: Identification using screening credentialing ability TEAD inhibition enhance provides roadmap strategies. See related commentary Johnson Haigis, p. 4005

Язык: Английский

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Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers

Nature Cancer, Год журнала: 2024, Номер 5(7), С. 1102 - 1120

Опубликована: Апрель 2, 2024

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available pharmacologic agents bind into lipid pocket TEAD, targeting indirectly via allosteric changes. However, consequences a direct pharmacological disruption interface between and TEADs remain largely unexplored. Here, we present IAG933 its analogs as potent first-in-class selective disruptors with suitable properties to enter clinical trials. Pharmacologic abrogation all four TEAD paralogs resulted in eviction from chromatin reduced Hippo-mediated transcription induction cell death. In vivo, deep tumor regression was observed Hippo-driven mesothelioma xenografts at tolerated doses animal models well Hippo-altered cancer outside mesothelioma. Importantly this also extended larger indications, such lung, pancreatic colorectal cancer, combination RTK, KRAS-mutant MAPK inhibitors, leading more efficacious durable responses. Clinical evaluation is underway.

Язык: Английский

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Expected and unexpected effects after systemic inhibition of Hippo transcriptional output in cancer

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 27, 2024

Abstract Hyperactivation of YAP/TAZ, the Hippo pathway downstream effectors, is common in human cancer. The requirement YAP/TAZ for cancer cell survival preclinical models, prompted development pharmacological inhibitors that suppress their transcriptional activity. However, systemic inhibition may sometimes have unpredictable patient outcomes, with limited or even adverse effects because action not simply tumor promoting but also suppressive some types. Here, we review role distinct populations, discuss impact inhibiting output on growth, and examine current developments inhibitors.

Язык: Английский

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New insights into the ambivalent role of YAP/TAZ in human cancers

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Май 22, 2023

Abstract Hippo signaling was first identified in Drosophila as a key controller of organ size by regulating cell proliferation and anti-apoptosis. Subsequent studies have shown that this pathway is highly conserved mammals, its dysregulation implicated multiple events cancer development progression. Yes-associated protein (YAP) transcriptional coactivator with PDZ-binding motif (TAZ) (hereafter YAP/TAZ) are the downstream effectors pathway. YAP/TAZ overexpression or activation sufficient to induce tumor initiation progression, well recurrence therapeutic resistance. However, there growing evidence also exert tumor-suppressive function context-dependent manner. Therefore, caution should be taken when targeting clinical trials future. In review article, we will give an overview their oncogenic roles various cancers then systematically summarize functions different contexts. Based on these findings, further discuss implications YAP/TAZ-based targeted therapy potential future directions. Graphical

Язык: Английский

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TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors

Cancer Research, Год журнала: 2023, Номер 83(24), С. 4112 - 4129

Опубликована: Ноя. 7, 2023

Abstract Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to long-term efficacy of direct inhibitors KRASG12C mutant in cancer. To identify potential mechanisms resistance, we applied a CRISPR/Cas9 loss-of-function screen observed loss multiple components Hippo tumor suppressor pathway, which acts suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired antiproliferative proapoptotic effects inhibitor (G12Ci) treatment KRASG12C-mutant cancer cell lines. Conversely, genetic suppression YAP1/WWTR1 (TAZ) enhanced G12Ci sensitivity. activity overcame KRAS dependency through two distinct TEAD transcription factor–dependent mechanisms, phenocopy effector signaling. First, stimulated ERK-independent genes normally regulated by ERK (BIRC5, CDC20, ECT2, FOSL1, MYC) promote progression cycle. Second, caused PI3K–AKT–mTOR signaling overcome apoptosis. was also YAP1/TAZ-TEAD activation. Accordingly, concurrent with pharmacologic synergistically antitumor vitro prolonged vivo. In summary, these observations reveal as crucial driver primary inhibition support use enhance KRAS-targeted therapies. Significance: compensates for signaling, establishing mechanistic basis KRASG12C-selective cancers. See related commentary Johnson Haigis, p. 4005

Язык: Английский

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Tyrosine phosphorylation-mediated YAP1-TFAP2A interactions coordinate transcription and trastuzumab resistance in HER2+ breast cancer

Drug Resistance Updates, Год журнала: 2024, Номер 73, С. 101051 - 101051

Опубликована: Янв. 9, 2024

Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation tyrosine kinase SRC identified be key modulator trastuzumab response. However, detailed regulatory mechanisms underlying activation-associated remain poorly understood. In present study, we discover that SRC-mediated YAP1 phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring BC. Inhibition activity disruption YTT complex sensitizes cells treatment vitro and vivo. Additionally, also identify co-occupies regions a series genes related directly regulates their transcriptions, including EGFR, HER2, H19 CTGF. Moreover, YTT-mediated regulation coordinated by activity. Taken together, our study reveals formation transcriptions are responsible for multiple associated resistance. Therefore, targeting HER2 signaling combination inhibition YTT-associated outputs could serve as strategy overcome caused activation.

Язык: Английский

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Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

Cells, Год журнала: 2024, Номер 13(7), С. 564 - 564

Опубликована: Март 22, 2024

Originally identified in Drosophila melanogaster 1995, the Hippo signaling pathway plays a pivotal role organ size control and tumor suppression by inhibiting proliferation promoting apoptosis. Large suppressors 1 2 (LATS1/2) directly phosphorylate Yki orthologs YAP (yes-associated protein) its paralog TAZ (also known as WW domain-containing transcription regulator [WWTR1]), thereby their nuclear localization pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established of mis-regulated tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development drug resistances. components at heart adaptations fuel resistance cancers for targeted therapies including KRAS EGFR mutants. The first U.S. food administration (US FDA) approval imatinib tyrosine kinase inhibitor 2001 paved way nearly 100 small-molecule anti-cancer drugs approved US FDA national medical products (NMPA). However, low response rate posed major hurdle to improving progression-free survival (PFS) overall (OS) cancer patients. Accumulating evidence has enabled scientists clinicians strategize therapeutic approaches targeting cells navigate through continuous monitoring evolution adaptations. In this review, we highlight emerging aspects cross-talk other drivers how information can be translated into combination therapy target broad range aggressive tumors resistance.

Язык: Английский

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Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 15, 2024

Abstract Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness evade autolysis, which, however, is shared by leukemic killing. Downregulation filamin A identified induce via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite requirements both cell types for induction, are more resistant inhibitors than malignant cells, potentially due higher expression drug-resistant transporter, MDR1, CTLs. As result, moderate inhibition stiffens but spares CTLs, allowing cytolyze without autolysis. Our findings hint force-based immunotherapeutic strategy against leukemia.

Язык: Английский

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A Single-Arm Phase 2 Trial of Trametinib in Patients with Locally Advanced or Metastatic Epithelioid Hemangioendothelioma

Clinical Cancer Research, Год журнала: 2024, Номер 30(20), С. 4584 - 4592

Опубликована: Март 6, 2024

Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib inhibitor MEK, critical kinase in We sought to evaluate effect trametinib patients EHE.

Язык: Английский

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Noncanonical role of Golgi-associated macrophage TAZ in chronic inflammation and tumorigenesis

Science Advances, Год журнала: 2025, Номер 11(4)

Опубликована: Янв. 22, 2025

Until now, Hippo pathway–mediated nucleocytoplasmic translocation has been considered the primary mechanism by which yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) coactivators regulate cell proliferation differentiation via enhanced associate domain (TEAD)-mediated target gene expression. In this study, however, we found that TAZ, but not YAP, is associated Golgi apparatus in macrophages activated Toll-like receptor ligands during resolution phase of inflammation. Golgi-associated TAZ vesicle trafficking secretion proinflammatory cytokines M1 macrophage independent pathway. Depletion tumor-associated promoted tumor growth suppressing recruitment tumor-infiltrating lymphocytes. Moreover, a diet-induced metabolic dysfunction–associated steatohepatitis model, macrophage-specific deletion ameliorated liver inflammation hepatic fibrosis. Thus, targeted therapies being developed against YAP/TAZ-TEAD are ineffective macrophages. Together, our results introduce as potential molecular for therapeutic intervention to treat progression chronic inflammatory diseases.

Язык: Английский

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