Abstract C185: CIP2A is a novel therapeutic target for an erlotinib derivative in EGFR wild-type NSCLC cells. Free

Rationale: Cancerous inhibitor of protein phosphatase 2A (CIP2A), a proto-oncogene inhibiting proteolytic degradation of c-MYC, is overexpressed in various types of human cancers, including lung cancer.

Objective: To determine if erlotinib and its derivative can inhibits EGFR mutation-negative NSCLC via CIP2A inactivation.

Methods: EGFR mutation-negative NSCLC cell lines (H358, H460, and H322) were treated with erlotinib or TD-19, an erlotinib derivative that closely resembled erlotinib structurally but devoid of tyrosine-kinase inhibitory activity. Apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with H460 xenografts.

Results: Erlotinib showed differential effects on apoptosis in 3 human NSCLC cell lines. Erlotinib induced significant apoptosis in H358 cell line; however, H460 and H322 cell lines showed resistance to erlotinib-induced apoptosis at all tested doses. Down-regulation of CIP2A, a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of erlotinib in H358 cell line. Erlotinib inhibited CIP2A in a dose- and time-dependent manner in sensitive NSCLC cells whereas no alterations in CIP2A were found in resistant cells. Overexpression of CIP2A upregulated phospho-Akt and protected H358 cells from erlotinib-induced apoptosis. In addition, silencing CIP2A by siRNA restored the effects of erlotinib in H460 cells. Moreover, adding okadaic acid, a PP2A inhibitor, abolished the effects of erlotinib on apoptosis in H358 cells. TD-19 had better effects than erlotinib on growth inhibition and apoptosis in erlotinib-resistant H460 and H322 cell lines through CIP2A-PP2A-Akt pathway. Overexpression of CIP2A upregulated phospho-Akt and protected H460 cells from TD-19-induced apoptosis. Moreover, adding okadaic acid, a PP2A inhibitor, abolished the effects of TD-19 on apoptosis in H460 cells. Furthermore, in vivo xenograft data showed that TD-19 inhibited the growth of H460 tumor but erlotinib had no effect on H460 tumor. TD-19 downregulated CIP2A and upregulated PP2A activity in H460 tumors, but erlotinib did not.

Conclusions: Inhibition of CIP2A determines the effects of erlotinib and its derivative on apoptosis in EGFR mutation-negative NSCLC. CIP2A may be useful as a therapeutic target for erlotinib and its derivative in EGFR mutation-negative NSCLC treatment.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C185.

Citation Format: Ting-Ting Chao, Cheng Yi Wang, Fang-Yu Chang, Yen-Lin Chen, Chung-Wai Shiau, Kuen-Feng Chen. CIP2A is a novel therapeutic target for an erlotinib derivative in EGFR wild-type NSCLC cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C185.