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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 271

tients, but almost inevitably tumours progress to an advanced castrate resistant stage [castration resistant
prostate cancer (CRPC)]. Mechanisms of progression to CRPC are varied, but a common theme is that AR
activity is retained and often amplified, despite very low (castrate) levels of circulating androgens. In a cer-
tain percentage of resistant tumours the AR itself is amplified, mutated or truncated, but this is not always
the case. The AR is a member of the Nuclear receptor (NR) superfamily of transcription factors, and NRs
share common cofactor proteins which act to increase or decrease their transcriptional activity - known
as coactivators and corepressors, respectively. These cofactors are frequently multifunctional proteins, and
AR cofactors include RNA splicing factors such as FUS, cytoplasmic chaperone and co-chaperone proteins
such as p23 and BAG-1L, cell cycle and transcriptional effectors such as Prohibitin and some CDKs, the
Hey proteins which are well-characterised Notch effectors, and tripartite motif proteins. We and others
have shown that amplification of coactivators and loss or dysregulation of corepressors are also mecha-
nisms of therapy resistance in prostate cancer. Interestingly we found that androgen treatment of prostate
cancer cells results in downregulation of certain corepressors, thus the AR itself may promote tumour
growth by downregulating its own repressors. Manipulation of AR cofactors is thus a valid therapeutic
strategy for CRPC, and we have demonstrated that both inhibition of coactivators and increasing levels
of corepressors can inhibit growth and invasion of prostate cancer cells, in vitro and in vivo. Other factors
that can affect AR levels and activity are microRNAs, which usually act by reducing levels of their target
mRNAs. They play vital roles in prostate cancer development, progression and metastasis and we hypoth-
esised that microRNAs that modulate AR activity in lethal CRPC represent novel therapeutic targets for
this disease. We used a high-throughput functional screen to systematically identify such microRNAs, and
have shown that microRNAs can affect AR either directly or by targeting key cofactors, including the core-
pressor Prohibitin. Inhibitors of AR-modulatory microRNAs dramatically reduces AR activity and growth,
migration and invasion of prostate cancer cells, and may thus represent novel prostate cancer therapeutics.
They also show additive effects with AR silencing or antiandrogen treatment, suggesting potential com-
binatorial applications for prostate cancer treatment. A major advantage of microRNAs is that they are
released from tumours into the circulation, where they can be detected and quantified. They thus also have
enormous potential as prognostic and predictive biomarkers.

11. Tyrosine Phosphorylation of nuclear PTEN in Glioma promotes therapeutic resistance
through DNA damage repair

Frank Furnari

Ludwig Institute for Cancer Research, University of California, San Diego, USA

Ionizing radiation (IR) and chemotherapy are standard of care treatments for glioblastoma (GBM) patients
and both result in DNA damage, however their clinical efficacy is limited due to therapeutic resistance.
Here, we identified a mechanism of such resistance mediated by nuclear PTEN phosphorylated on tyro-
sine 240 (pY240-PTEN) by FGFR2 kinase. pY240-PTEN is rapidly elevated and bound to chromatin in
response to IR treatment and facilitates the recruitment of DNA repair protein, RAD51, to sites of damage.
Thus, cells with high levels of pY240-PTEN are resistant to DNA damage and blocking Y240 phosphoryla-
tion with FGFR inhibitors confers radiation sensitivity to tumors and extends survival in GBM preclinical
models. The central importance of PTEN Y240 phosphorylation in mediating DNA damage repair is fur-
ther highlighted by the extreme radiation sensitivity of Y240F-PTEN knock-in mice. These results suggest
that FGFR-mediated phosphorylation of PTEN Y240 is a key mechanism of radiation resistance and is an
actionable target for improving radiotherapy efficacy in GBM patients.