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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [exp2]

ABSTRACT: Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [exp2]

PROVIDER: PRJNA856122 | ENA |

REPOSITORIES: ENA

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [exp2]

Project description:The effect of radiation therapy (RT) on tumor immunity in PDAC is not well understood. To better understand if RT can prime antigen-specific T cell responses, we analyzed human PDAC tissues and PDAC GEMMs. In both settings, we found little to support evidence of RT-induced T cell priming. Using in-vitro systems, we found tumor stromal components, including fibroblasts and collagen, synergize to both blunt RT efficacy and impair RT-induced interferon signaling. Focal Adhesion Kinase (FAK) inhibition rescued RT efficacy in-vitro and in-vivo, leading to tumor regression, T cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of VS-6063 in combination with SBRT in PDAC patients (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in GEMMs. Finally, the addition of checkpoint immunotherapy to RT and FAKi in animal models led to complete tumor regression and long-term survival.

2022-10-09 | GSE207536 | GEO

Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade.

Project description:Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade.

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [in vitro]

Project description:Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [in vitro]

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [in vitro]

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [scRNA seq data from mice]

Project description:Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [scRNA seq data from mice]

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [scRNA seq data from mice]

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Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.

Project description:The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor-stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival.SignificanceCheckpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711.

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ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p826_PND_A549]

Project description:Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5) as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevents resistance to FAK inhibitors, significantly enhancing the efficacy of antitumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.

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ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p697_ERK5]

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-09 | GSE207718 | GEO