Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significant benefits to patients with non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations; however, acquired resistance limits their long-term efficacy. Therefore, it remains an urgent requirement to discover the underlying mechanisms and investigate novel therapeutic strategies for overcoming the resistance to EGFR TKIs. The present study aimed to determine the mechanism underlying the resistance of NSCLC cells to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, the osimertinib-resistant NSCLC cell sub-line HCC827/OR was established in the present study. It was found that the expression levels of Bcl-2 and Bcl-xL were significantly upregulated in resistant cells compared with sensitive cells. Furthermore, the suppression of Bcl-2 and Bcl-xL through small interfering RNA-mediated gene knockdown or using a small molecule specific inhibitor ABT-263 re-sensitized HCC827/OR cells to osimertinib treatment. Moreover, the combined treatment of HCC827/OR cells with ABT-263 and osimertinib enhanced the rate of cell apoptosis through the mitochondrial apoptotic pathway. Finally, ABT-263 was able to overcome the resistance of osimertinib in xenograft tumor models. In conclusion, these findings may provide an improved concept for the development of a novel combined therapeutic strategy for the treatment of NSCLC resistance to EGFR TKIs.

Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors

“…This is attributed to tumor protein 53 (TP53) mutation which could be found in our three cell lines, thus presenting a spectrum of more resistant cell lines that represent the majority of HNSCC. Similar to our findings, in NSCLC cell lines with EGFR mutations, Lu et al discovered an upregulation of Bcl-2 and Bcl-x L as a mechanism to of 13 escape cell death via tyrosine kinase inhibitors and sensitized them via BH3 mimetics [22]. Interestingly, while a p53 gene mutation correlated with poor survival in NSCLC patients, sole Bcl-2 abnormalities showed no significant influence on the prognosis, consorting with our findings that isolated Bcl-2 inhibition had no impact on our NSCLC cell lines' vitality [23].…”

Therapeutic potential of the novel Bcl‐2/Bcl‐XL dual inhibitor, APG1252, alone or in combination against non‐small cell lung cancer

“…In this study, the combination of osimertinib and APG1252-M1 was also effective in decreasing the survival and inducing apoptosis of In agreement with previous findings using other Bcl-2/Bcl-X L inhibitors, 16,17 we also demonstrated that the combination of…”

“…16 Similar results were also generated in another EGFRm cell line, HCC827, with osimertinib resistance. 17 A recent phase Ib study using the combination of osimertinib and ABT-263 for advanced EGFRm NSCLC with prior tyrosine kinase inhibitor exposure demonstrated the safety and feasibility of the combination at the recommended phase II dose, together with clinical efficacy. 18 The dual inhibitor of Bcl-2 and Bcl-X L , APG1252 (pelcitoclax) and its in vivo active metabolite, APG1252-M1 (or APG-1244), were shown to have remarkable single-agent antitumor effects in acute myeloid leukemia, small cell lung cancer and gastric cancer.…”

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

“…A phase II trial of gefitinib with chemotherapy or antiangiogenesis as front-line therapy is no-going in BIM-del EGFR-mutant NSCLC patients (NCT03267654). Other potential drugs like selective BCL-2/BCL-xL inhibitors, as proapoptotic agents, could re-sensitize resistant cell lines to osimertinib in vitro and improve PFS in pretreated T790M patients [33][34][35]. Clinical trials are needed in EGFRmutant patients with BIM-del.…”