Jathal Maitreyee K, Mudryj Maria, Dall'Era Marc A, Ghosh Paramita M
Research Service, VA Northern California Health Care System, Mather, CA, USA.
Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA.
Cell Mol Life Sci. 2024 Dec 27;82(1):24. doi: 10.1007/s00018-024-05540-5.
Neoadjuvant therapy (NAT) has been studied in clinically localized prostate cancer (PCa) to improve the outcomes from radical prostatectomy (RP) by 'debulking' of high-risk PCa; however, using androgen deprivation therapy (ADT) at this point risks castration resistant PCa (CRPC) clonal proliferation. Our goal is to identify alternative NAT that reduce hormone sensitive PCa (HSPC) without affecting androgen receptor (AR) transcriptional activity. PCa is associated with increased expression and activation of the epidermal growth factor receptor (EGFR) family, including HER2 and ErbB3. The FDA-approved HER2 inhibitor lapatinib has been tested in PCa but was ineffective due to continued activation of ErbB3. We now demonstrate that this is due to ErbB3 being localized to the nucleus in HSPC and thus protected from lapatinib which affect membrane localized HER2/ErbB3 dimers. Here, we show that the well-established, well-tolerated potassium-sparing diuretic amiloride hydrochloride dose dependently prevented ErbB3 nuclear localization via formation of plasma membrane localized HER2/ErbB3 dimers. This in turn allowed lapatinib inactivation of these dimers via inhibition of its target HER2, which dephosphorylated ERK1/2 and inhibited survival. Amiloride combined with lapatinib significantly increased apoptosis at relatively low doses of both drugs but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with using ADT as NAT in HSPC.
新辅助治疗（NAT）已在临床局限性前列腺癌（PCa）中进行研究，旨在通过对高危PCa进行“减瘤”来改善根治性前列腺切除术（RP）的疗效；然而，此时使用雄激素剥夺疗法（ADT）有导致去势抵抗性PCa（CRPC）克隆增殖的风险。我们的目标是确定可替代的NAT，其可减少激素敏感性PCa（HSPC），同时不影响雄激素受体（AR）的转录活性。PCa与表皮生长因子受体（EGFR）家族（包括HER2和ErbB3）的表达增加和激活有关。FDA批准的HER2抑制剂拉帕替尼已在PCa中进行测试，但由于ErbB3的持续激活而无效。我们现在证明，这是由于ErbB3在HSPC中定位于细胞核，因此免受影响膜定位的HER2/ErbB3二聚体的拉帕替尼的作用。在此，我们表明，成熟且耐受性良好的保钾利尿剂盐酸阿米洛利通过形成质膜定位的HER2/ErbB3二聚体，剂量依赖性地阻止了ErbB3的核定位。这反过来又使拉帕替尼能够通过抑制其靶标HER2使这些二聚体失活，从而使ERK1/2去磷酸化并抑制细胞存活。阿米洛利与拉帕替尼联合使用在两种药物的相对低剂量下显著增加了细胞凋亡，但不影响AR的转录活性。因此，我们的数据表明，阿米洛利和拉帕替尼联合使用可以靶向HSPC肿瘤，而不存在将ADT用作HSPC的NAT所带来的问题。
