PTEN Loss in mCRPC: Caution Surrounding mTOR, PI3K, and AKT Inhibition


Panelists share caution toward use of mTOR-, PI3K-, and AKT-targeted therapies in the setting of PTEN loss in metastatic CRPC.


Evan Y. Yu, MD: Before we talk about PARP inhibitors, which of course we're going to be talking about, I want to talk about a pathway that I think has had excitement in the field but has lost shininess for a while and we know that P10 is lost in a lot of prostate cancer patients and downstream PI3 kinase pathway, AKT mTOR. I know Andy, you've worked in this area somewhat. What's going on this field?

Andrew J. Armstrong, MD, MSc: This is an oldie but goodie to bring back. I've been working on it since my ASCO [American Society of Clinical Oncology] investigator award,2005.

Evan Y. Yu, MD: Yes, I remember this stuff.

Andrew J. Armstrong, MD, MSc: I was motivated by Charles Sawyer's finding, Gleevec for CML and focused on P10 losses maybe being synthetically lethal for an mTOR inhibitor, rapalogs, and that's not the case. When you block mTOR, there's all sorts of redundant feedback mechanisms. You get upregulation of AR, you can see PSA going up, not down. And we learned that the hard way by studying rapalogs in phase 2 clinical trials, which all failed miserably, and then we moved upstream to PI3 kinase and AKT inhibitors, monotherapies, all failed miserably, and we have a large number of publications showing that. The field has in general moved towards combination therapied, whether that's with an immune therapy because PI3 kinase regulates immune evasion as well. Or an AR combination, Johann de Bono's ipatasertib abiraterone combo. But again, that's not been successful because there's other back door and reciprocal pathways beyond those 2 so it could be part of a future cocktail but right now it's not showing efficacy and large foundation chart review with some clinical outcomes has shown no benefits to doing that in clinical practice. Just because you see P10 loss on your foundation report doesn't mean you should reach for an mTOR or a AKT or PI3 kinase inhibitor.

Transcript edited for clarity.

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