Combined targeting of EGFR and HER2 against prostate cancer stem cells

Abstract

Progression of prostate cancer has been associated with EGFR and HER2 activation and to tumorinitiating cells contribution toward chemotherapy resistance. We investigated the efficacy of a dual intervention against EGFR and HER2 to deplete the tumor-initiating cells, optimize the chemotherapy management and prevent the progression of castration-resistant prostate cancer (CRPC) cells. Using DU145, PC3, and 22Rv1 CRPC cell lines, biochemical analysis revealed activation of EGFR, HER2, MAPK, and STAT3 in DU145 and 22Rv1, and AKT and SRC in DU145 and PC-3. pSTAT3 nuclear staining was observed in DU145 xenografts and in 12 out of 14 CRPC specimens. The in vivo dual targeting of ErbB receptors with Cetuximab and Trastuzumab combined with chemotherapy caused an effective antitumor response in DU145 xenografted mice displaying STAT3 activation; conversely PC-3 bearing mice experienced tumor relapse. The potentiating of in vivo cytotoxic effect in DU145 model was accompanied by a significant decrease of prostatosphere-forming capacity assessed in vitro on residual tumor cells. Additionally, combined treatment in vitro with Cetuximab, Trastuzumab and chemotherapy negatively affected DU145 and 22Rv1 sphere formation, suggesting the critical function of ErbB receptors for tumor-initiating cells proliferation; no effect on PC-3 clonogenic potential was observed, indicating that other receptors than EGFR and HER2 may sustain PC3 tumor-initiating cells. These findings provided the preclinical evidence that the dual inhibition of EGFR and HER2 by targeting tumorinitiating cells may improve the efficacy of the current chemotherapy regimen, bringing benefits especially to castration-resistant patients with activated STAT3, and preventing disease progression.

A Personalized Genomics Approach of the Prostate Cancer

“…We found that ERBB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2, a.k.a., HER2 ) is expressed in-antiphase in “N” with respect to nodules “A” and “B” but in-phase between these two nodules. This finding justifies the reports that ERBB2 activation is associated with tumor-initiating cells contribution and progression of prostate cancer [ 69 ].…”

METTL14 promotes prostate tumorigenesis by inhibiting THBS1 via an m6A-YTHDF2-dependent mechanism

“…Despite the initial response to androgen deprivation therapy (ADT), the majority of patients relapse with a poor prognosis stage of castration-resistant prostate cancer (CRPC). Patients with CRPC cannot be cured currently and the mortality remains high [ 3 , 4 ]. Thus, understanding of the mechanisms underlying PCa progression is essential for molecular diagnosis and targeted therapy.…”

Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA

“…The higher number of significant concurrently mutated genes in other molecular pathways may explain the decreased efficacy of PARP inhibitors in prostate cancer harboring BRCA1 mutations compared to those with BRCA2 mutation. For example, ERBB2 alterations co-segregate strongly with BRCA1 and are known to be associated with tumor aggressiveness in primary prostate cancer, tumor progression and invasion in advanced prostate cancer, and shorter time to castration-resistance ( 8 ). Similarly, alterations in NOTCH1 also co-segregate with BRCA1 .…”