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• W2013316302 abstract "Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAVirtually all patients undergoing standard-of-care androgen deprivation therapy (ADT) for recurrent prostate cancer (PCa) will develop castration-resistant prostate cancer (CRPC). Despite overexpression of the epidermal growth factor receptor (EGFR) family - especially EGFR, ErbB2 and ErbB3 - in all stages of PCa progression, the dual-kinase EGFR/ErbB2 inhibitor lapatinib (GW572016) failed in Phase 2 trials in hormone-naive and CRPC patients. Here, we investigated mechanisms of lapatinib resistance using the CWR22 (‘R22’, hormone-naive) and CWR22-Rv1 (‘Rv1’, CRPC) models of PCa progression.R22 or Rv1 tumors were implanted (s.c.) in male athymic nu/nu mice, castrated or left intact and treated daily with vehicle or 100mg/kg lapatinib (oral gavage). Tumors were collected at the study’s end and analyzed (Western Blot/WB, immunohistochemistry/IHC).With Ki67 staining, compared to R22 tumors, Rv1 tumors were more proliferative and unaffected by castration or lapatinib. R22 tumors regressed after castration but not lapatinib. As in human patients, lapatinib resistance was observed in hormone-naive R22 and CRPC Rv1 tumors thus validating our experimental model.First we asked why Rv1 tumors proliferated rapidly. Rv1 tumors expressed 2-fold more ErbB3 than R22 tumors (WB). We previously showed that ErbB3 overexpression increased proliferation (Chen et al., Canc. Res, 70(14):5994-6003, 2010) - hence we attribute the rapid growth of Rv1 tumors to high ErbB3. Castration reduced EGFR, phosphorylated Akt and Erk in R22 but not in Rv1 tumors - decreased activation of these kinases may mediate the effects of castration on tumor growth. Rv1 tumors expressed alternately-spliced variants of androgen receptor (AR) that cause castration-resistance and less PSA than R22 tumors.Next, we asked why EGFR/ErbB2 inhibition failed in Rv1 tumors, despite EGFR's prominence in this tumor type. Lapatinib reduced intratumoral PSA levels in intact R22 mice but increased it in Rv1 mice. Lapatinib also increased EGFR and phosphorylated Akt in intact Rv1 but not R22 tumors. We hypothesize that, in Rv1 tumors, increased EGFR induces Akt phosphorylation which, we have shown earlier, regulates AR transcriptional activity and increases PSA expression. In contrast, in castrated Rv1 mice, lapatinib also increased ErbB3 levels. In Rv1 tumors, castration increased nuclear ErbB3 whereas in R22 tumors it increased cytoplasmic ErbB3 (IHC).Our results indicate that lapatinib may have failed in castrated Rv1 mice due to increased overall ErbB3 but in castrated R22 tumors due to increased cytoplasmic ErbB3. Regardless, the result is heightened ErbB3-related activity, which may cause increased proliferation and eventual drug failure. A pan-ErbB drug which also inhibits ErbB3, e.g. dacomitinib, can successfully overcome EGFR/ErbB2 resistance, as demonstrated in vitro.Citation Format: Maitreyee K. Jathal, Thomas M. Steele, Benjamin A. Mooso, Leandro S. D'Abronzo, Salma Siddiqui, Christiana Drake, Paramita M. Ghosh. Increased ErbB3 and EGFR activity mediate lapatinib resistance in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3335. doi:10.1158/1538-7445.AM2014-3335" @default.
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• W2013316302 date "2014-09-30" @default.
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• W2013316302 title "Abstract 3335: Increased ErbB3 and EGFR activity mediate lapatinib resistance in prostate cancer" @default.
• W2013316302 doi "https://doi.org/10.1158/1538-7445.am2014-3335" @default.
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