PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

Abstract

Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC. Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines. Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation. Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.

Gene expression in circulating tumor cells reveals a dynamic role of EMT and PD-L1 during osimertinib treatment in NSCLC patients

“…Herein, we report that relatively high levels of PIM-1 transcripts were detected in all time points of our study, without any statistically significant difference among them; this observation strongly suggests that this kinase in constantly highly expressed in CTCs and, in parallel, its expression is not affected by osimertinib. However, a strong positive correlation was found between PIM-1 and VIM expression mostly at baseline in contrast to PD samples; although, there is no a clear explanation for this finding, it could be speculated that, according to previous evidence, PIM-1 might indirectly promote cell proliferation by regulating signaling pathways such as IL-6/STAT3 15 , 53 .…”

“…We also examined PIM-1 expression in CTCs in this patient cohort since it is a promising novel therapeutic target in NSCLC. Many studies indicate the synergistic effects of combination of PIM inhibitor and osimertinib either by preventing the activation of oncogenic signaling pathways 15 or acting through the inhibition of the phosphorylation of STAT3 52 . Herein, we report that relatively high levels of PIM-1 transcripts were detected in all time points of our study, without any statistically significant difference among them; this observation strongly suggests that this kinase in constantly highly expressed in CTCs and, in parallel, its expression is not affected by osimertinib.…”

“…Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) is a kinase that is implicated in the control of cancer cell proliferation, migration and apoptosis, by interacting with several other oncogenic signaling pathways and its oncogenic and prognostic role is already proven in various types of cancer including lung cancer 14 . Several studies have shown that PIM-1 indirectly affects EGFR signaling and that its inhibition synergistically improved the efficacy of other inhibitors and subsequently patients’ treatment outcomes 14 , 15 .…”

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

“…112 This combination approach has also been shown in non-small-cell lung cancer (NSCLC), where AZD-1208 and osimertinib (an EGFR inhibitor) elicited synergistic effects with respect to cell viability and phosphorylation of STAT3 (ref. 115 ), which, if replicated in PCa, could prevent STAT3-driven promotion of aggressive prostate cancer features. 86 PIM AND RADIOTHERAPY PCa radiotherapy resistance is often linked to and may be attributed to aberrations in the expression of various signaling pathways and genes involved in cell growth and cell death, including downregulation of DOC2/DAB2 (double C2 domain; DAB adaptor protein 2) and P53 (tumor protein P53) and upregulation of MDM2 (ref.…”

Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer

“…The activation of signalling nodes such as STAT3 and YAP1 as well as the upregulation of different RTKs such as CDCP1 and AXL upon EGFR inhibition also result in EGFR drug resistance (Chaib et al, 2017;. A recent study showed that combining PIM and EGFR inhibitors in EGFR-mutation positive NSCLC cell lines was moderately synergistic but decreased STAT3 phosphorylation, an important signalling node in therapy resistance (Bracht et al, 2019).…”