EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition

Abstract

BIM (BCL2L11) is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGF receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in EGFRmutant forms of non-small cell lung cancer (NSCLC). Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKIs gefitinib and erlotinib and therefore conferring an inherent drug-resistant phenotype. Indeed, patients with NSCLC, who harbored this host BIM polymorphism, exhibited significantly inferior responses to EGFR-TKI treatment than individuals lacking this polymorphism. In an attempt to correct this response defect in the resistant group, we investigated whether the histone deacetylase (HDAC) inhibitor vorinostat could circumvent EGFR-TKI resistance in EGFR-mutant NSCLC cell lines that also harbored the BIM polymorphism. Consistent with our clinical observations, we found that such cells were much less sensitive to gefitinib-induced apoptosis than EGFR-mutant cells, which did not harbor the polymorphism. Notably, vorinostat increased expression in a dose-dependent manner of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the EGFR mutant, EGFR-TKIresistant cells. In xenograft models, while gefitinib induced marked regression via apoptosis of tumors without the BIM polymorphism, its combination with vorinostat was needed to induce marked regression of tumors with the BIM polymorphism in the same manner. Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of EGFR-mutant NSCLC where resistance to EGFR-TKI is associated with a common BIM polymorphism. Cancer Res; 73(8); 2428-34. Ó2013 AACR.

DUSP1 Expression Induced by HDAC1 Inhibition Mediates Gefitinib Sensitivity in Non–Small Cell Lung Cancers

“…Overexpression of HDACs might mediate drug resistance like cisplatin, etoposide, and vincristine (28,29). HDACi MS-275 has been reported to restore gefitinib sensitivity in lung cancer cells through upregulation of E-cadherin expression (30), and SAHA could restore BIM function and gefitinib sensitivity in resistant NSCLC cells harboring the BIM deletion polymorphism (31). In our study, HDAC1 was overexpressed in gefitinib-resistant H1975, PC9/IR, and HCC827/IR cells, and its knockdown could overcome gefitinib resistance and induce DUSP1 expression in vitro and in vivo.…”

Podoplanin-Positive Cancer-Associated Fibroblasts in the Tumor Microenvironment Induce Primary Resistance to EGFR-TKIs in Lung Adenocarcinoma with EGFR Mutation

“…Wang and colleagues (13) reported that hepatocyte growth factor (HGF) confers an intrinsic resistance to EGFR-TKI by activating MET, which restores the phosphorylation of downstream MAPK-ERK1/2 and the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in lung adenocarcinoma with EGFR mutations. Ng and colleagues (14,15) also reported that a BIM-deletion polymorphism is associated with intrinsic resistance to EGFR-TKIs.…”

CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance

“…The presence of T790M-resistant mutations or other rare exon 20 mutations has been described in only a very small percentage of patients before exposure to EGFR-TKI treatment (19). Several studies showed that many EGFR-mutated NSCLC patients carry a common germline polymorphism of the proapoptotic gene BIM that results in deletion of the death-inducing BH3 domain of BIM and intrinsic resistance to EGFR-TKI therapy (20,21), although the finding could not be confirmed in another study (22). Moreover, BIM expression is a good marker in predicting TKI resistance (23,24).…”