Page 103 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

SDIRSACR Oncology Insights

SESSION 2

PERSONALIZED ANTICANCER TREATMENT THROUGH TARGETING SIGNALING PATHWAYS

P05

TFEB Controls Chemoresistance in NSCLC

Muhlis Akman 1,2,3 , Tatiana Chontorotzea4, Thomas Mohr4, Chiara Riganti1

1Molecular Biotechnology Center “Guido Tarone”, University of Torino,Torino, Italy
2Neuroscience Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Türkiye
3Computational Drug Design Center (HITMER), Bahçeşehir University, İstanbul, Türkiye
4Center for Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

Keywords: ABCA1, MDR, NSCLC, TFEB

Background: In NSCLC, the effectiveness of chemo-immunotherapy is influenced by the dysregulated expression
of ABC transporters, including the overexpression of ABCC1 and the reduced expression of ABCA1. While ChIP-Seq
studies in endothelial cells have identified several ABC transporters as transcriptional targets of transcription factor
EB (TFEB), its role in cancer remains unclear. TFEB, a leucine zipper protein, is a key regulator of lysosomal biogenesis
and autophagy, and emerging evidence suggests its involvement in modulating the immune recognition of cancer cells
by the host immune system. In this study, we investigated if TFEB affects the response to chemotherapy and to Vγ9δ2
T- lymphocytes in non-small cell lung cancer (NSCLC).
Materials and Methods: The influence of TFEB/ABCC1/ABCA1 expression on the survival of NSCLC patients was
examined using data from the TCGA-LUAD cohort and a retrospective cohort from our institution. Human NSCLC cells
with TFEB silencing (shTFEB) were assessed for ABC transporter expression, chemosensitivity, and immune-mediated
cytotoxicity. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB
tumors and the tumor immune microenvironment were investigated in Hu-CD34+ mice through single-cell RNA
sequencing.
Results: TFEBlowABCA1lowABCC1high phenotype proved to be the worst prognosis for the NSCLC patients. ChIP assay
indicated that ABCA1 is a direct target of TFEB. By reducing the pERK1/2, shTFEB cells had reduced ERK-1/2-mediated
activation of SREBP2, which modulates genes of cholesterol homeostasis. As such, TFEB silencing down-regulated
genes of cholesterol synthesis, decreased expression and activity of the cholesterol/IPP transporter ABCA1, the efflux
of IPP, and the NSCLC killing by Vγ9δ2 T-lymphocytes. In parallel, shTFEB cells had increased expression of ABCB1
and ABCC1 and significantly higher IC50 values for cisplatin. The results of immune xenografts confirmed that shTFEB
tumors were more resistant to cisplatin than wild-type counterparts. The combination of cisplatin and NZ was effective
in reversing the chemo-immuno-resistance of shTFEB tumors.
Conclusions: This study revealed that TFEB plays a crucial role in regulating sensitivity to chemotherapy and immune-
mediated killing in NSCLC. Incorporating TFEBlowABCA1lowABCC1high signature into the diagnostic workflow could
provide valuable insights for optimizing treatment selection on an individual basis in NSCLC patients.

Acknowledgments and funding: Supported by the AIRC (Grant No. IG21408).

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