Abstract 920: KW-2450, a novel IGF-1R/IR inhibitor, enhances the antitumor effect of lapatinib, letrozole or 4-hydroxy-tamoxifen in breast cancer cells.
Authors: Umehara Hiroshi , Koizumi Fumito , Maekawa Yoshimi , Shimizu Makiko , Nakamura Hiroaki , Ota Toshio , Nara Shinji , Takahashi Takeshi , Kanda Yutaka , Shiraishi Norihiko , Akinaga Shiro , Shiotsu Yukimasa , Soga Shiro 
Published: August 2014

[Background] Both the insulin-like growth factor-1 receptor (IGF-1R) and insulin receptors (IR) have been found to be promising targets for breast cancer therapy because their activation has been associated with breast cancer development, progression and drug resistance. KW-2450, a potent inhibitor of both IGF-1R and IR, is currently in clinical development in combination with lapatinib and letrozole for HER2-positive advanced or metastatic breast cancer. To support the rationale for evaluating this combination, we examined the combined effects of KW-2450 and lapatinib, a HER2/EGFR inhibitor, in a HER2/IGF-1R-expressing breast cancer cell line, and the combined effects of KW-2450 and either letrozole or 4-hydroxy-tamoxifen in a hormone-dependent breast cancer cell line.

[Results] KW-2450 and lapatinib showed a strong synergistic effect against the HER2/IGF-1R double-positive cell line, MDA-MB-361, probably caused by enhanced caspase-3/7 activation, compared to the treatment with lapatinib alone. In this setting, KW-2450 completely inhibited the phosphorylation of IGF-1R/IR, whereas lapatinib mostly inhibited the phosphorylation of HER2. Interestingly, neither KW-2450 nor lapatinib inhibited Akt phosphorylation, however, the combined treatment showed a remarkable inhibition of Akt phosphorylation. In fact, KW-2450 showed a potent combined anti-tumor effect in vivo. Furthermore, a microarray analysis identified other biomarkers, such as Ki67, survivin and TIMP3, whose expression levels were changed by the combined treatment with KW-2450 and lapatinib.

In an aromatase-dependent cell line, MCF-7-Ac1, the combination of KW-2450 and letrozole showed a strong synergistic effect. Moreover, the combination of KW-2450 and 4-hydroxy-tamoxifen showed a synergistic effect in an estrogen-dependent cell line, MCF-7.

[Conclusions] Our results suggest that the combination of KW-2450 and lapatinib in HER2/IGF-1R double-positive breast cancers and that of KW-2450 and anti-hormone agents in hormone-dependent breast cancers are highly effective, exhibiting a synergistic anti-cancer activity. Therefore, KW-2450 may be a promising platform for carrying out combination therapy for breast cancer.

Citation Format: Hiroshi Umehara, Fumito Koizumi, Yoshimi Maekawa, Makiko Shimizu, Hiroaki Nakamura, Toshio Ota, Shinji Nara, Takeshi Takahashi, Yutaka Kanda, Norihiko Shiraishi, Shiro Akinaga, Yukimasa Shiotsu, Shiro Soga. KW-2450, a novel IGF-1R/IR inhibitor, enhances the antitumor effect of lapatinib, letrozole or 4-hydroxy-tamoxifen in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 920. doi:10.1158/1538-7445.AM2013-920