SIU 2017: Mechanisms of Treatment Induced Resistance

Lisbon, Portugal ( Dr. Evans gave an elaborate talk on the various mechanisms of treatment induced resistance in castrate resistant prostate cancer (CRPC). He began his talk by describing the many potential targets for treatment in the androgen axis, and resistance mechanisms. These include androgen receptor (AR) mutations, loss of AR, AR DNA binding, CYP17A1 expression, and more.

In a study where metastatic CRPC sites were biopsied from various organs, it was noted that AR was amplified in 54%, 58% and 73% of bone, lymph node and hepatic lesions, respectively. Moreover, it was noted that 43% of these biopsies had non-adenocarcinoma histologies (t-SCNC and IAC). When looking specifically at these new and unique histologies, it was demonstrated that their overall survival was significantly worse when compared to that of the “standard” adenocarcinoma histology (11.1 vs. 25.8 months, p=0.018). AR amplifications were found across all histologic subtypes, both adenocarcinoma and non-adenocarcinoma. Furthermore, it was noted that serum neuroendocrine marker levels were high and similar in both IAC and t-SCNC histologies, and their gene expression signatures were completely different when compared to adenocarcinoma. 

Due to therapeutic resistance in CRPC, Dr. Evans continued to state that it is essential to develop co-targeting strategies against androgen synthesis, AR splice variants, and metabolic resistance. Studies have shown that AKR1C3 activation confers resistance to Enzalutamide in prostate cancer (PC). Inhibition of AKR1C3 activation overcomes resistance to Abiraterone in advanced PC.

Dr. Evans moved on and discussed on the AR. It has 8 exons, contains 920 amino acids and 4 structurally and functionally distinct domains: the N terminus, C terminus, DNA binding domain and small hinge region. There are several AR variants, including the famous AR-V7 which confer resistance to enzalutamide and abiraterone. It was discovered that an old drug by the name of Niclosamide inhibits AR variant expression and overcomes enzalutamide resistance in CRPC.

Another mechanism of resistance is by autophagy (self-eating). At signs of cellular stress, the cell start a process of autophagy where it preserves its energy by degrading and recycling some of its cytoplasmic components. It has been seen that targeting autophagy overcomes enzalutamide resistance in CRPC cells and improves therapeutic response in a xenograft model.

Other new strategies targeting the AR include specifically targeting the nuclear receptors of androgens. It was discovered that the retinoic acid receptor-related orphan receptor (ROR) is overexpressed in >50% of CRPC tumors by immunohistochemistry (IHC). These receptors are gnomically altered in metastatic tumors, and directly control AR gene expression. ROR drive AR expression and represent a therapeutic target in CRPC.

Dr. Evans concluded his talk by stating that mCRPC treatment results in new, poor prognosis phenotypes. The new found histologies of IAC and t-SCNC are an aggressive cancer and account for 42% of all mCRPC samples. AR-V7 and AKR1C3 are resistance mechanism variants in CRPC and can be measured in blood, and can serve as potential predictive biomarkers. Lastly, ROR levels can be detected by sequencing or IHC and it can be inhibited with new compounds to treat CRPC.

Presented by: Christopher Evans

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre.Twitter: @GoldbergHanan at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal