CAPTURE-CAPIVASERTIB AND PROSTATE CANCER TARGETING: UNRAVELING RESISTANCE ELEMENTS

M. Zavatti¹, V. Serafin¹, L. Antolini¹, S. Bresolin², L. Reggiani Bonetti³, S. Marmiroli¹ | ¹Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; ²Pediatric Hematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, Padua University, Padua, Italy; ³Department of Medical and Surgical Sciences. University of Modena and Reggio Emilia, Modena, Italy

Prostate cancer is the second most commonly diagnosed cancer in men and the third cause of cancer-related deaths in European men. Invariably, cancer secondary to genomic aberration is initially dependent on androgen receptor for growth. Therefore, castration by hormone therapies, such as androgen deprivation therapy combined to inhibitors of the androgen receptor, abiraterone or enzalutamide, remain the first therapeutic choice. Nevertheless, recurrence and progression to metastatic castration-resistant prostate cancer is frequent, and these patients have very short survival due to limited treatment options, with only one third surviving five years after diagnosis. Recently, several clinical studies (such as CAPItello 281) associated abiraterone to the firstin-class, ATP-competitive, pan AKT inhibitor capivasertib, with encouraging results. However, it is well known that adaptive signaling can cause attenuation of PI3K/AKT inhibitors efficacy, reducing clinical outcome. By means of SILAC-based proteome mapping, our study reveals that capivasertib alters the expression of several proteins involved in the endocytic pathway, such as Dynamin II, Rab5 as well as the transferrin receptor, helping cancer cells to evade apoptosis. Moreover, we demonstrate that inhibition of AKT prompts complete down-modulation of microRNA-145, a well-known anti-oncogenic and a major downregulated microRNA in prostate cancer. Remarkably, by the miRNet algorithm we found that several targets of miR-145 are downstream effectors or upstream activators of the PI3K/AKT pathway. Accordingly, we observed a dramatic Ras overexpression, as well as reactivation of signaling. As proof of principle, we have confirmed these findings in cell lines engineered to silence miR-145 and also in vivo in a xenograft model of prostate cancer. Altogether, these findings reveal the existence of a novel circuit of adaptive resistance to AKT inhibition in prostate cells. Mechanistically, our results indicate that inhibition of AKT triggers downregulation of miR-145 which in turn upregulates RAS expression, leading to paradoxical reactivation of signaling that limits drug efficacy.