Abstract 4618: PIM kinases drive cell adhesion mediated drug resistance in prostate cancer
Authors: Flores Caitlyn , Chauhan Shailender , Miranti Cynthia , Cress Anne , Rogers Gregory , Warfel Noel 
Published: March 2024

Introduction: Castration-resistant prostate cancer (CRPC) is an incurable and lethal progression of the disease that does not respond to any treatment options. Cell adhesion to the extracellular matrix (ECM) activates survival pathways, allowing cancer cells to evade anti-cancer therapy, a phenomenon known as cell adhesion-mediated drug resistance. Bone, which is the primary site of prostate cancer metastasis, is known to be enriched in laminin, a ubiquitous ECM protein. In addition, laminin binding integrins, α6β1 and α3β1, are the major integrins expressed in CRPC, suggesting that laminin-dependent adhesion provides a survival advantage. Based on these findings, activation of the laminin-binding integrin, α6β1, is an intriguing factor mediating resistance to therapy in CRPC. PIM1 is an oncogenic Ser/Thr kinase that is elevated in CRPC and is known to promote resistance to therapy. In contrast, to many pro-survival kinases, PIM kinases do not possess any obvious regulatory domains. Current evidence suggests that PIM1 is constitutively active when it is expressed, so PIM1 expression level directly correlates with its catalytic activity. Despite this fact, little is known about the internal and external mechanisms that dictate PIM1 protein levels and spatial activation in cancer cells. Here, we identify PIM1 as a key survival signal that contributes to cell adhesion-mediated drug resistance.

Experimental procedures: Supporting the importance of this signaling axis in human tumors, multiplex IHC of a TMA containing prostate adenocarcinoma and CRPC bone metastases to show that integrin α6 and PIM1 are coexpressed and spatially correlated in primary and metastatic prostate cancer. To examine the spatiotemporal dynamics of PIM1 during cell adhesion, We developed a kinase activity reporter (PIMKAR) to monitor PIM catalytic activity in live cells. Because we observed PIM was highly localized to the membrane in patient tumors, we tagged PIMKAR with a myristylation sequence to specifically measure PIM activity at the membrane vs cytosol. Immunofluorescence and biochemical techniques were used to demonstrate the effect of PIM1 on mitophagy and oxidative stress.

Conclusions: We demonstrate that activation of integrin α6β1 downstream of cell adhesion stabilizes PIM1 by blocking its proteasomal degradation. The resulting upregulation of PIM1 serves to reduce oxidative stress through complementary mechanisms reducing mitochondrial fragmentation and increasing the removal of damaged mitochondria by increasing mitophagy. Mechanistically, PIM1 upregulates BNIP3 to enhance mitophagy and thereby reduce oxidative stress in the cell. Together, these results expand our understanding of the mechanisms regulating PIM1 activation and provide evidence for the use of PIM inhibitors in bone mCRPC and other cancers where laminin is a major component of the ECM

Citation Format: Caitlyn Flores, Shailender Chauhan, Cynthia Miranti, Anne Cress, Gregory Rogers, Noel Warfel. PIM kinases drive cell adhesion mediated drug resistance in prostate 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 4618.