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(6_Suppl):Abstract nr 5201.