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Lorenzin et al. J Transl Genet Genom 2019;3:5. I https://doi.org/10.20517/jtgg.2019.01 Page 7 of 12

ALTERNATIVE PROGRAMS OF RESISTANCE
The observation that a portion of prostate cancer samples overexpresses SPINK1, a trypsin inhibitor
that protects the gastrointestinal tract from protease degradation, opened up to the possibility that a
gastrointestinal (GI)-lineage specific expression program is activated to promote castration resistance.
Accordingly, studies showed that SPINK overexpression is associated with worse prognosis and more rapid
progression of resistant tumors [95-98] and a subclass of CRPC expresses high levels of hepatocyte nuclear
[99]
factor 4-gamma (HNF4G) and 1-alpha (HNF1A) . These two master transcription factors sustain a GI
transcriptional program in prostate cancer, present non-overlapping cistrome with AR, and their exogenous
expression leads to resistance to androgen depletion and to enzalutamide in prostate cancer cell lines and
[99]
xenograft models .

An alternative pathway that could sustain growth of prostate cancers is the WTN signaling pathway. Indeed,
similar to colon cancers, mutations in CTNNB1 (encoding for β-catenin) genes, which lead to ligand-
independent activation of the pathway, were identified in prostate cancer samples [100,101] . Recent sequencing
efforts comparing the genomic feature of primary and metastatic castration resistant tumors detected
mutations in major components of the WNT signaling as being enriched in the latter [19,22] . Moreover, high
levels of WNT ligands are found in mCRPC samples and in vitro work supports a direct interaction between
β-catenin and AR and a role for β-catenin in enhancing AR transcriptional activity [58,102-105] .

CONCLUSION
Potent therapies often trigger resistance mechanisms that present or are facilitated by distinct genomic
or molecular settings. Whereas functional studies are needed to reveal the mechanistic features of drug
resistance, the role of large-scale genomic studies on contemporary cohorts of patients can nominate
structural events associated to resistance that can eventually turn into biomarkers for treatment options.
Recent work has also suggested that complex structural events possibly involving non-coding areas of the
genome can contribute to our knowledge of disease progression. AR enhancer duplication [18,33,34] and RB1
exon 7-17 tandem duplication [106] leading to AR overexpression and RB1 protein loss respectively are relevant
examples of events discovered through whole genome sequencing studies. Similarly, SNPs located in non-
coding inter- or intragenic regions were shown to be associated with specific subtypes of prostate cancer and
with disease aggressiveness [107-110] .

The application of new therapeutic strategies to treat CRPC patients will further lead to the emergence of
alternative mechanisms of resistance different from those identified so far. PARP and immune checkpoint
inhibition in CRPC patients harboring defect in DNA repair pathways, such as homologous recombination
and mismatch repair, and CDK12 inactivation [19,111,112] will profoundly shape the mutational landscape of
prostate cancer in the future. The timely detection of mutations remains an issue of utmost importance
for patient care. While liquid biopsy based studies provide promising venues to regularly monitor patients
treatment response and to track tumor dynamics, proper assay design is required in order not to miss
relevant new markers of resistance.

DECLARATIONS
Authors’ contributions
Wrote this review: Lorenzin F, Demichelis F

Availability of data and materials
Not applicable.