PIM1 inhibitor synergizes the anti-tumor effect of osimertinib via STAT3 dephosphorylation in EGFR-mutant non-small cell lung cancer

Abstract

Background: An increasing amount of evidence has demonstrated that combined or multiple targeted therapies could bring about more durable clinical outcomes, and it is known that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance is related to bypass activation. This study aims to explore a specific solution for third-generation EGFR-TKI resistance caused by bypass activation, and to examine the antitumor effects of the combination of a novel inhibitor CX-6258 HCl with osimertinib, along with its underlining mechanisms.Methods: A bioinformatics analysis was performed to detect the relations between the provirus integration site for Moloney murine leukemia virus 1 (PIM1) expression and prognosis of lung cancer. The EGFRmutated lung cancer cell lines were treated with the combination of CX-6258 HCl and osimertinib to analyze cell proliferation using the Cell Counting Kit-8, colony formation, and in vivo experiments. Cell migration was analyzed using wound healing and Transwell assays. The apoptosis level was detected using Annexin V-propidium iodide flow cytometry. The expression levels of EGFR and STAT3 were determined using Western blot analysis.Results: High expression level of PIM1 was related to the poor prognosis of non-small cell lung cancer (NSCLC). The combined administration of osimertinib and CX-6258 HCl significantly inhibited cell proliferation and migration and effectively induced apoptosis in lung cancer cells. It was more efficient in suppressing EGFR activation and phosphorylation of STAT3 compared with osimertinib treatment alone.Furthermore, it showed a durable efficacy in a xenograft model. Conclusions:This study showed that PIM1 is a poor prognostic factor for NSCLC. CX-6258 HCl is a potential molecular inhibitor to sensitize the antitumor effects of osimertinib through the inhibiting of the phosphorylation of STAT3 in NSCLC.

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

“…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.…”

Osimertinib-Induced Unilateral Diffuse Alveolar Hemorrhage in a Patient With Pulmonary Adenocarcinoma

“…This was a rare case of osimertinib-induced DAH. To our knowledge, there were only two osimertinib-induced and four other EGFR-TKI-induced DAH cases (Table 1) [1,[4][5][6][7][8]. We could not find a report of DAH induced by other EGFR-TKIs; afatinib and dacomitinib, and anti-EGFR antibodies; cetuximab and panitumumab.…”

“…Although the mechanisms of drug-induced DAH remains unidentified, a direct toxicity to type II pneumocytes, tracheal epithelial cells and vascular endothelial cells by cytotoxic drugs and activation of immune system cells may play a key role [ 7 ]. In some previous literatures of TKI-induced DAH, this cytotoxic mechanism was assumed as the cause of DAH [ 4 , 6 , 8 ].…”

“…Differential cell counts in the BALF may be a potential and useful marker of sensitivity to steroid and prognosis in DAH. There were only two reports of differential cell counts in the BALF of EGFR-TKI-induced DAH [ 4 , 7 ]. A 56-year-old Japanese man with 90% of lymphocytes and 10% of neutrophils in the BALF improved after high dose of methylprednisolone [ 4 ].…”

“…Two months after the Osimertinib-Induced DAH J Med Cases. 2021;12 (7):295-299 initiation of osimertinib, both primary tumor in the right upper lobe and metastatic lesions in the bilateral lungs reduced, and no ground-grass opacity was detected (Figs. 1b, 2a).…”