Abstract 457: Persister cell state-associated lncRNA signatures in non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis and a 5-year survival rate of 9%. Targeted therapies for oncogene-dependent tumors like tyrosine kinase inhibitors (TKIs) improve outcomes yet their clinical efficacy is often limited by occult drug-tolerant persister cells (DTPCs), causing recurrence. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides and typically non-protein coding. They regulate cellular functions by interacting with substrates through their complex secondary structures. Their deregulation is linked to oncogenesis and therapy resistance. While their role in lung cancer has been documented, their involvement in the DTPC state remains unexplored. Our study aims to investigate the role of lncRNAs in mechanisms that drive failure to targeted therapy in NSCLC. We comprehensively analyzed single-cell RNA-seq data from 49 NSCLC biopsies, pre- and during TKI therapy (residual disease, RD). We identified several lncRNAs that were significantly, differentially expressed in RD when compared to treatment naïve (TN) tumors. We orthogonally validated these findings in a minimum of 2 lung cancer cell lines in TN or DTPCs (9-15 days upon TKI exposure in culture) [p<0.05, absolute log2 fold change > 0.3]. We found that MALAT1, HCG11, and EPB41L4A-AS1 (lncRNA-UP signature) displayed significantly increased expression in RD relative to TN tumors and parental cell lines. We also found significant downregulation of LUCAT1 and LINC00152 (lncRNA-DOWN signature) in RD samples. We further performed Kaplan-Meier survival analysis in an independent set of RD samples stratified by differential expression of our lncRNA signatures (n=18/group). The analysis showed improved overall survival in patients whose DTPCs expressed a high level of the lncRNA-UP signature (hazard ratio, HR=0.56; log-rank test p=0.0331). We did not observe significant differences in survival for the lncRNA-DOWN signature. We additionally performed survival analysis using the GEPIA database for lung adenocarcinoma (primarily TN, n= 239/group). Consistently, the analysis showed improved overall survival for high levels of the lncRNA-UP signature (HR=0.71; p=0.029), whereas high levels of the lncRNA-DOWN signature were indicative of inferior outcomes (HR=1.4, p=0.046). We systematically identified DTPC-associated lncRNA signatures from our unique DTPC cohort, indicating that deregulation of lncRNA expression may play a role in acquired drug resistance in lung cancer. DTPC-associated lncRNA expression patterns are linked to differential overall survival, suggesting a possible tumor-suppressive or promoting role and highlighting their potential as predictive biomarkers and therapeutic targets. Further investigation into the functional roles of these lncRNAs and their interplay with coding molecules is warranted. Citation Format: Jovanka Gencel-Augusto, Wei Wu, Trever G. Bivona. Persister cell state-associated lncRNA signatures in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 457.