Data from Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer

• DOI: 10.1158/1078-0432.c.6525675.v1
• Publication Date: 2023-04-01T06:31:08Z
• Authors: Rasmi R. Mishra; Nevin Belder; Suhail A. Ansari; Merve Kayhan; Hilal Bal; Umar Raza; Pelin G. Ersan; Ünal M. Tokat; Erol Eyüpoğlu; Özge Saatci; Pouria Jandaghi; Stefan Wiemann; Ayşegül Üner; Caglar Cekic; Yasser Riazalhoss...; Özgür Şahin

<div>Abstract<p><b>Purpose:</b> Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms tamoxifen and provide actionable drug targets overcoming resistance.</p><p><b>Experimental Design:</b> Whole-transcriptome sequencing, downstream pathway analysis, repositioning approaches were used modulators [here: phosphodiesterase 4D (PDE4D)] resistance. Clinical data involving tamoxifen-treated patients with cancer assess the impact PDE4D sensitization role was tested <i>in vitro</i> vivo</i>. Cytobiology, biochemistry, functional genomics tools elucidate PDE4D-mediated resistance.</p><p><b>Results:</b> PDE4D, which hydrolyzes cyclic AMP (cAMP), significantly overexpressed both MCF-7 T47D tamoxifen-resistant (TamR) cells. Higher expression predicted worse survival (<i>n</i> = 469, <i>P</i> 0.0036 DMFS; <i>n</i> 561, 0.0229 RFS) remained independent prognostic factor RFS multivariate analysis 132, 0.049). Inhibition by either siRNAs or pharmacologic inhibitors (dipyridamole Gebr-7b) restored sensitivity. Sensitization achieved via cAMP-mediated induction unfolded protein response/ER stress leading activation p38/JNK signaling apoptosis. Remarkably, acetylsalicylic acid (aspirin) be sensitizer using approach shown reverse targeting PDE4D/cAMP/ER axis. Finally, combining suppressed tumor growth better than individual groups vivo</i>.</p><p><b>Conclusions:</b> plays pivotal acquired blocking cAMP/ER stress/p38-JNK <i>Clin Cancer Res; 24(8); 1987–2001. ©2018 AACR</i>.</p></div>