GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiation-sensitize primary and brain-metastatic lung adenocarcinoma tumors

Abstract

In non-small cell lung cancer (NSCLC) treatment, targeted therapies benefit only a subset of NSCLC, while radiotherapy responses are not durable and toxicity limits therapy. We find that a GABA(A) receptor activator, AM-101, impairs viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing an ex vivo chip, AM-101 is as efficacious as the chemotherapeutic docetaxel, which is used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a survival benefit to mice bearing NSCLC intracranial tumors. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, and utilization of ubiquitin-binding protein p62. A targeted-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 triggering autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. HighlightsO_LIActivating GABA(A) receptors intrinsic to lung primary and metastatic brain cancer cells triggers a cytotoxic response. C_LIO_LIGABA(A) receptor activation works as well as chemotherapeutic docetaxel in impairing lung cancer viability ex vivo. C_LIO_LIGABA(A) receptor activation increases survival of mice bearing lung metastatic brain tumors. C_LIO_LIA selective-autophagic response is stimulated by GABA(A) receptor activation that includes multimerization of GABARAP and Nix. C_LIO_LIEmploying a new nanomolar affinity peptide that abrogates autophagosome formation inhibits cytotoxicity elicited by GABA(A) receptor activation. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/569295v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1df2f4eorg.highwire.dtl.DTLVardef@19ac26forg.highwire.dtl.DTLVardef@1533986org.highwire.dtl.DTLVardef@e59653_HPS_FORMAT_FIGEXP M_FIG C_FIG