Abstract B260: Antitumor activity of HM781-36B, an irreversible pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer cells

• Published in: Molecular cancer therapeutics 2009-12, Vol.8 (12_Supplement), p.B260-B260
• Main Authors: Nam, Hyun-Jin, Kim, Hwang-Phill, Yoon, Young-Kwang, Hur, Hyung-Seok, Kim, Maeng-Sup, Lee, Gwan-Sun, Han, Sae-Won, Oh, Do-Youn, Im, Seock-Ah, Kim, Tae-You, Bang, Yung-Jue
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-B260

Background: HM781-36B is a novel quinazoline-based irreversible pan-HER inhibitor. Although the effects of many other pan-HER inhibitors (CI-1033, PF00299804, BMS-599626, BMS-690514 and JNJ-28871063) have been studied in various types of cancer, data regarding the use of pan-HER inhibitors to treat gastric cancers are limited. In this study, we evaluated the therapeutic potential of HM781-36B for the treatment of gastric cancers by testing its in vitro and in vivo efficacy. In addition, we further characterized its activity when administered in combination with chemotherapeutic agents. Methods: Experiments were conducted in gastric cancer cell lines. Enzyme activity assay was conducted to determine the IC50 values of HM781-36B for kinase inhibition and MTT assay was used for determining growth inhibitory effect. Cell cycle distribution was analyzed by flow cytometry and apoptotic effect was measured by annexin V assay. And N87 xenograft model was used to see tumor regression effect. Western blot analysis was used to verify mechanism of this compound. Results: We found that HM781-36B suppressed the proliferation of HER2-amplified gastric cancer cell lines (SNU216 and N87) potently when compared to the effects of other HER family tyrosine kinase inhibitors (gefitinib, lapatinib, BIBW-2992 and CI-1033). Furthermore, we found that HM781-36B inhibited the phosphorylation of HER family and their downstream signaling proteins, which resulted in apoptosis through the caspase-mediated mitochondrial pathway and G1 arrest. The apoptotic process requires the induction of the proapoptotic BH3-only BCL2 family member, BIM, and HM781-36B led to a dramatic increase in the BIM level in SNU216 and N87 cells. Consistent with these in vitro findings, HM781-36B showed exceptional anti-tumor activity in a xenograft model of N87 cells. Furthermore, HM781-36B exerted synergistic effects when administered in combination with 5-fluorouracil or cisplatin in both HER2 amplified cells and HER2 non-amplified gastric cancer cells. Conclusion: Taken together, these data suggest that HM781-36B may be useful as a targeted therapy for the treatment of HER2 amplified gastric cancer as well as a chemosensitizer of cytotoxic chemotherapeutic agents used to treat gastric cancer, even in HER2 non-amplified gastric cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B260.