GABA(A) Receptor Activation Drives GABARAP-Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors

Debanjan Bhattacharya; Riccardo Barrile; Donatien Kamdem Toukam; Vaibhavkumar S Gawali; Laura Kallay; Taukir Ahmed; Hawley Brown; Sepideh Rezvanian; Aniruddha Karve; Pankaj B Desai; Mario Medvedovic; Kyle Wang; Dan Ionascu; Nusrat Harun; Subrahmanya Vallabhapurapu; Chenran Wang; Xiaoyang Qi; Andrew M Baschnagel; Joshua A Kritzer; James M Cook; Daniel A Pomeranz Krummel; Soma Sengupta

doi:10.3390/cancers16183167

GABA(A) Receptor Activation Drives GABARAP-Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors

Cancers (Basel). 2024 Sep 15;16(18):3167. doi: 10.3390/cancers16183167.

Authors

Debanjan Bhattacharya¹, Riccardo Barrile², Donatien Kamdem Toukam¹, Vaibhavkumar S Gawali¹, Laura Kallay¹, Taukir Ahmed³, Hawley Brown⁴, Sepideh Rezvanian³, Aniruddha Karve⁵, Pankaj B Desai⁵, Mario Medvedovic⁶, Kyle Wang⁷, Dan Ionascu⁷, Nusrat Harun⁸, Subrahmanya Vallabhapurapu⁹, Chenran Wang¹⁰, Xiaoyang Qi⁹, Andrew M Baschnagel¹¹, Joshua A Kritzer⁴, James M Cook³, Daniel A Pomeranz Krummel^{12

13}, Soma Sengupta^{12

13

14}

Affiliations

¹ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
² Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45221, USA.
³ Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA.
⁴ Department of Chemistry, Tufts University, Medford, MA 02144, USA.
⁵ Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH 45229, USA.
⁶ Department of Environmental & Public Health Sciences, University of Cincinnati, Cincinnati, OH 45267, USA.
⁷ Department of Radiation Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
⁸ Division of Biostatistics & Epidemiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
⁹ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
¹⁰ Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
¹¹ Department of Human Oncology, University of Wisconsin, Madison, WI 53792, USA.
¹² Department of Neurosurgery, University of North Carolina, Chapel Hill, NC 27599, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁴ Department of Neurology, University of North Carolina, Chapel Hill, NC 27517, USA.

Abstract

In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity.

Keywords: GABA receptor; GABARAP; Nix; autophagy; benzodiazepine; brain metastasis; lung cancer; p62; radiotherapy.

Abstract

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