P1.02-065 Elucidating the Role of PIM Kinase and Its Therapeutic Potential in NSCLC

Abstract

PIM kinases are a family of three serine/threonine kinases: PIM1, PIM2 and PIM3 that have been shown to play a role in tumorigenesis. PIM1 is a downstream effector of oncoproteins ABL and JAK/STAT and regulator of BCL2/BAD and CXCR4. PIM activity is synergistic with the PI3K/Akt/mTOR pro-survival pathway and PIM2 has been shown to phosphorylate translational repressor 4E-BP1 and p70S6 independently of the PI3K pathway. Furthermore a synergism between PIM kinases and c-Myc has been reported. Here we investigate the expression of PIM1/PIM2/PIM3 in NSCLC cell lines and patient matched normal/tissue samples. The effect of a novel combined inhibitor of PI3K/mTOR/PIM kinases (IBL-301) on cell signaling, cell death and proliferation is also examined. PIM1/PIM2/PIM3 expression were examined by Western blot analyses in NSCLC cells (H1975 and H1838). Additionally, the frequencies of PIM1/PIM2/PIM3 expression in NSCLC patient tumor and matched normal adjacent samples (n=31) were investigated. The effectiveness of IBL-301 on cell signaling, cell viability and proliferation were examined by Western blot analysis, cell titre blue and BrdU assay respectively. All three PIM isoforms were detected in the lung cancer cell lines tested. Similarly, all three PIM isoforms were expressed across the 31 NSCLC patient tumor and match normal adjacent tissue samples. To investigate this further PIM1 staining of FFPE tumor and match normal tissue from this cohort is currently underway. In two lung cancer cell lines, H1975 and H1838, IBL-301 was found to have a dose dependent effect on proliferation/viability with IC50 values in the nanomolar range. Additionally, western blot analyses have indicated that these novel drugs can suppress the phosphorylation of key players in cell signaling pathways linked to tumorigenesis including pAkt, p4E-BP1 and peIF4B. This is the first study to investigate the expression of all 3 isoforms of PIM in lung cancer specifically. All 3 isoforms were abundantly expressed across cells lines and patient tumor samples. Observed PIM expression in the immune cells of normal adjacent tissue may indicate a role in inflammation. This finding coupled with the promising in vitro data demonstrate the therapeutic potential of targeting PIM in NSCLC.