Abstract 5201: Characterization of PDLIM2 in non-small cell lung cancer

Abstract Introduction: PDZ and LIM domain protein 2 (PDLIM2) acts as tumor suppressor by downregulating NF-κB and STAT3 signaling, modulating inflammation, immune response, and cell survival. Mouse model studies have demonstrated that downregulation of PDLIM2 leads to PD-1 immune blockade and chemotherapy resistance. We present a large clinical and molecular characterization of PDLIM2 expression in non-small cell lung cancer (NSCLC). Methods: NextGen sequencing of DNA (whole exome) /RNA (whole transcriptome) was performed for NSCLC (Total N = 29126; Adenocarcinoma -A, N = 15765, Squamous -S, N = 6416) patient tumors submitted to Caris Life Sciences (Phoenix, AZ). Mutations were defined as pathogenic SNVs/indels. Samples were stratified by PDLIM2 expression quartiles (in transcripts per million TPM) for all NSCLC tumors (Q4: H, Q1: L). PD-L1 expression 22C3; Positive (+): tumor proportion score (TPS) ≥1%was assessed by IHC. High tumor mutational burden (TMB-high) set as ≥10 mutations per Mb. Cell infiltration in the tumor microenvironment was estimated by QuantiSEQ. Gene expression profiles were analyzed for transcriptional signatures predictive of response to immunotherapy (T cell-inflamed). Real-world overall survival was assessed from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined subpopulations. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons (p 0. 05). Results: Median PDLIM2 expression was higher in NSCLC-A compared to NSCLC-S (15. 3 vs 13. 6 TPM, p 0. 001). PDLIM2-AL had a lower prevalence of EGFR mutations than PDLIM2-AH (15. 5% vs 19. 4%, p 0. 01), but the opposite pattern was observed for STK11 (21. 5% vs 11. 2%), RB1 (7. 5% vs 3. 8%), TP53 (62. 9% vs 52. 8%), KEAP1 (18. 4% vs 10. 9%), and SMARCA4 (9. 15 vs 4. 5%) alterations (all p 0. 001). PDLIM2-AL tumors had decreased PD-L1+ (L: 52. 4% vs H: 58. 4% p 0. 001) but increased TMB-High status (L: 40. 9% vs H: 28. 5%, p 0. 001). PD-L1+ and TMB-H frequency did not vary with PDLIM2 expression in NSCLC-S. In both NSCLC-A and -S tumors, PDLIM2H had increased infiltration of NK cells, macrophages, dendritic cells, T cells, neutrophils, monocytes, and B cells compared to PDLIM2L (all p 0. 05), in addition to increased T cell-inflammed scores (p 0. 001). PDLIM2-AH was associated with improved overall survival (OS) (median 21. 7 vs L: 15. 6 months; p 0. 001; Hazard ratio HR = 0. 825, 95% Confidence Interval CI 0. 765 - 0. 889) and time on pembrolizumab treatment (median 6. 2 vs L: 5. 6 months; p = 0. 009; HR = 0. 825 95% CI 0. 714 - 0. 953). No difference in OS was observed between PDLIM2-SH vs L tumors (H: 14. 8 vs L: 14. 0 months; p = 0. 37; HR = 0. 95, CI 0. 85-1. 06). Conclusions: NSCLC-A with high PDLIM2 expression have a unique mutational profile, increased immune cell infiltration and favorable OS. Therapeutic strategies for targeting PDLIM2 to modulate NF-κB and STAT3 signaling should be further explored. Citation Format: Karam Ashouri, Harris Krause, Andrew Elliott, Stephen V. Liu, Patrick C. Ma, Balazs Halmos, Zhaoxia Qu, Gutian Xiao, Ari Vanderwalde, Jorge J. Nieva. Characterization of PDLIM2 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 (6Suppl): Abstract nr 5201.