Abstract 2567: An analysis of proviral insertion site of Moloney murine leukemia virus, PIM1, kinase expression and clinical outcomes in renal cell carcinoma

Abstract

Abstract Background: Wild-type Proviral Insertion Site of Moloney Murine Leukemia Virus 1 Kinase (PIM1) is a constitutively active serine/threonine kinase that inhibits apoptosis and promotes cell cycle progression, proliferation, angiogenesis, invasion, and migration. Due to constitutive activation, PIM1 is regulated at transcription and degradation. We have previously shown PIM1 protein levels are elevated in clear cell renal cell carcinoma (ccRCC) compared to normal kidney and that PIM1 inhibition induces tumor regression in pre-clinical models. Current approved therapies for ccRCC do not inhibit PIM1. We hypothesized that high PIM1 expression will adversely affect clinical outcomes in ccRCC. Methods: Whole transcriptome sequencing (WTS) data in the Caris Life Sciences database were examined for PIM1expression and overall survival (OS; defined as time from diagnosis to last contact or death). We assessed PIM1 in primary and metastatic ccRCC, and the impact on survival in ccRCC and papillary RCC. Differentially expressed genes (DEGs) associated with high PIM1 were also determined. Results: PIM1, in the highest quintile, was associated with a shorter OS (869 vs 1738 days; HR 2.629; CI 1.495 - 4.611; p<0.001; N=147) in ccRCC. PIM1 is enriched in metastatic (median 7.62 transcripts per million (TPM), CI 6.35 - 9.26) vs primary (median 5.07 TPM; CI 4.28 - 6.45; p=0.0025) RCC. Upregulated DEGs associated with high PIM1 are involved in the extracellular matrix. IL-6 expression, known to correlate with worse outcomes, was 6.5-fold higher in PIM1 high vs PIM1 low (13.2 vs 2.1 TPM, p<0.0001) RCC. High PIM1 was associated with poor survival following checkpoint inhibition (HR 3.714, 95% CI 1.339 - 10.303, p=0.007) and a trend towards poorer survival following mTOR inhibition and VEGF inhibition. PIM1 did not affect survival in papillary RCC. Conclusions: Real-word data show that high PIM1 correlates with poorer survival in ccRCC but not in papillary RCC. This effect likely persists independent of treatment received. PIM1 enrichment in metastatic ccRCC, and associated DEGs, suggest that PIM1 influences the extracellular matrix to promote metastases. The correlation between IL-6expression and PIM1 supports our prior data that an IL-6/JAK/STAT/PIM1 pathway is involved in ccRCC. Citation Format: Sheldon L. Holder, Galina Lagos, Benedito A. Carneiro, Anthony Mega, Andre De Souza, Rana R. McKay, Andrew Elliott, Chadi Nabhan, Stephanie L. Graff. An analysis of proviral insertion site of Moloney murine leukemia virus, PIM1, kinase expression and clinical outcomes in renal cell carcinoma [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 2567.