Abstract 1323: Identification of conditions of lapatinib effectiveness in prostate cancer.
Authors: Jathal Maitreyee K. , Mooso Benjamin A. , D'Abronzo Leandro S. , Siddiqui Salma , Chen Liqun , van Spyck Elyse , Madhav Anisha , Ghosh Paramita M. 
Published: August 2014

Abstract
ABSTRACT Lapatinib has been used in multiple clinical trials of either hormone-naïve men with prostate cancer (PCa) or in patients who have progressed to castration resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT). Although lapatinib as a single-agent showed no overall positive effect in hormone-naive PCa, a small subset of unselected CRPC patients experienced PSA decline ∼50% with lapatinib treatment, with one patient remaining on this drug &gt;45 months (Whang, Y.E. et al, 2011. Urol Oncol). The current investigation had been undertaken to determine whether lapatinib may benefit any select group of patients with PCa. Studies in vitro and in animal models supported the observation that lapatinib was ineffective in the presence of androgens; however, in low-androgen conditions, only androgen-dependent LNCaP PCa cells, but not CRPC cells, responded to lapatinib. Since lapatinib is a dual inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) and a closely related member, ErbB2, hence we investigated the effect of this drug on the EGFR family. Comparison of the various cell lines that did or did not respond to lapatinib demonstrated that those that did not respond to lapatinib had very high inherent EGFR and ErbB3 activity, whereas LNCaP cells did not. More importantly, unlike its CRPC sublines C4-2 and LNCaP-AI, which were less responsive to lapatinib compared to LNCaP, the parental line experienced an increase in ErbB3 during androgen deprivation. Overexpression of ErbB3 induced resistance to lapatinib even in LNCaP cells, indicating an increase in the levels of RTKs as a potential cause for lapatinib resistance. Indeed, lapatinib treatment resulted in an overall increase in the levels of EGFR and/or ErbB2 in all the cell lines tested, even in LNCaP cells that do respond to lapatinib. Thus, our data demonstrate that (i) lapatinib is ineffective in PCa expressing high ErbB3 and (ii) among those with low intrinsic ErbB3, lapatinib is effective only in tumors where ErbB3 levels increase upon androgen withdrawal. Our results show that the critical window of opportunity for employing lapatinib and other dual EGFR/ErbB2 inhibitors is when ErbB3 levels are rising, but not once they have already increased. Since ErbB3 can be detected in the serum of patients with PCa, the increase of this RTK during ADT should be tested in future studies as a predictive marker of lapatinib response.
Citation Format: Maitreyee K. Jathal, Benjamin A. Mooso, Leandro S. D'Abronzo, Salma Siddiqui, Liqun Chen, Elyse van Spyck, Anisha Madhav, Paramita M. Ghosh. Identification of conditions of lapatinib effectiveness in prostate cancer. [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 1323. doi:10.1158/1538-7445.AM2013-1323