Saturday, September 20, 2008

mTOR, MAPK, and cancer

Recent studies are making it increasingly apparent that cancer is really many different diseases – hundreds actually – in the sense that there are hundreds of distinct problems at a molecular level that can result in the symptoms of cancer in a large variety of tissue types. It is necessary to regard all these problems as distinct diseases, because different techniques will be necessary to deal effectively with each one.

One of the things we are now understanding is that it is not simply mutations in a few specific genes that account for most different cancers. Instead, each different type of cancer can be attributed to mutations in one or several genes randomly chosen from a larger set that collectively defines some specific signaling "pathway" in a cell. Or perhaps even several interrelated pathways.

See here for one account of some of the latest research on this. I'd like to discuss the papers that cover this research, but first I'd like to discuss some slightly earlier research that provides a simpler look at the issue.

I've already written about one particular pathway of special importance, the one associated with mTOR. That discussion, from last April, is here.

As you recall, mTOR is a serine/threonine kinase. The pathway in which it plays a prominent part regulates the growth, proliferation, motility, and survival of cells. And also angiogenesis. From that list it should be obvious why malfunctions in the pathway can give rise to cancer. The pathway, in turn, integrates input from a number of upstream pathways, such as those involving intercellular signaling molecules like insulin, IGF-1, and mitogens.

The name mTOR is short for mammalian target of rapamycin. Rapamycin, also known as sirolimus, is a bacterial product that was originally of interest for its antifungal properties. It was subsequently found to have immunosuppressive and antiproliferative properties. These properties, in turn, are a consequence of the fact that rapamycin binds to a protein complex called mTOR complex 1 (mTORC1). The antiproliferative properties, of course, are due to the importance of mTOR in regulating cell proliferation and motility.

All this stuff is well known to cancer biologists and not new. In particular, much research has been devoted to finding useful inhibitors of mTOR. Unfortunately, however, the research hasn't been as successful at actually treating cancer as might have been hoped:

A Role For MAPK Inhibitors Combined With MTORC1 Inhibitors (8/21/08)
Nearly a decade ago, while it was being tested as an immunosuppressive agent to prevent organ rejection in transplant patients, the drug rapamycin was also discovered to have anti-tumor properties. Since then, several rapamycin analogs known as mTOR (mammalian target of rapamycin) inhibitors have been tested in clinical trials for the treatment of various types of cancer.

But despite promising early results, mTOR inhibitors have proven less successful than originally expected.

The problem is that the mTOR inhibitors that have been tried as anti-cancer drugs also seem to stimulate another pathway that promotes cell growth and proliferation:
Now research led by scientists at Beth Israel Deaconess Medical Center (BIDMC) identifies a previously unrecognized problem faced by these agents when it comes to attacking cancers. ... [T]he new findings show that at the same time that rapamycin analogs are halting tumor growth by inhibiting the mTOR protein complex 1 (mTORC1), they are activating the MAPK (mitogen-activated protein kinase) pathway -- thereby encouraging cancer cell survival.

The MAPK pathway has also been under intensive investigation in connection with cancer. As the name implies, kinases in this pathway are activated by mitogens – external signals that promote mitosis. These kinases also affect cell survival and apoptosis. So it's reasonable to guess that adding a MAPK inhibitor to an mTOR inihibitor might counteract the MAPK-stimulating effect of the mTOR inhibitors.

Are you with me? Anyhow, what the new research does is show how there's a feedback loop that connects mTOR inhibition with MAPK activation.

Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. ... We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway.

PI3K is another important signaling kinase about which there is a lot of other interesting current research – which we'll get around to discussing at some point. Ras is a G protein known to be very important in cancer because it activates MAPK pathways.

Are you beginning to get the picture of how complicated cancer can be, due to the interaction of pathways?

Fortunately, the research also shows that MAPK inhibition can offset problems due to mTOR inhibition:
[P]harmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors.

Another research group has already confirmed the same thing, using the same MAPK inhibitor (PD0325901):

Anti-tumor Effects Are Enhanced By Inhibiting Two Pathways Rather Than One (8/21/08)
In the second study, Cory Abate-Shen and colleagues, at Columbia University College of Physicians and Surgeons, New York, and the University of Medicine & Dentistry of New Jersey, Piscataway, show that simultaneous inhibition of the mTOR and MAPK signaling pathways inhibited the in vitro growth of prostate cancer cell lines and the in vivo growth of prostate tumors in a mouse model of prostate cancer.

Here's their research paper:

Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model.

AKT is yet another family of serine/threonine kinases, often associated with mTOR, that is deeply involved in tumorigenicity. There's a lot of recent research on it that should also be discussed... some other time.

Further reading:

From Metabolism to Oncogenes and Back - Part II – 3/21/08 blog post that discusses many cancer-related signaling pathways, including mTOR, AKT, PI3K, Ras, and their connection with metabolism
Arkaitz Carracedo, Li Ma, Julie Teruya-Feldstein, Federico Rojo, Leonardo Salmena, Andrea Alimonti, Ainara Egia, Atsuo T. Sasaki, George Thomas, Sara C. Kozma, Antonella Papa, Caterina Nardella, Lewis C. Cantley, Jose Baselga, Pier Paolo Pandolfi (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer Journal of Clinical Investigation DOI: 10.1172/JCI34739

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Blogger Allyson said...

very interesting stuff. Im a new graduate student working with rapamycin and trying to mechanistically understand what's happening. With my Rapamycin treatments (treating mice with Rapa followed by TPA topcially) I still see AKT (at serine 473)activation. Is this perhaps because there is no feedback inhibition of IRS-1 thus PI3K is able to phosphorylate Akt. Or perhaps rapamycin isn't affecting mTORC2 complex which is also responsible for phosphorylation of Akt. It is such a complicated picture and I still need to do some immunoprecipitations to figure some more of it out. your blog was of great interest.

5/21/2009 05:04:00 PM  
Blogger Charles Daney said...

Apologies for not responding to the above sooner. Fell through the cracks.

However, I'm not in a position to really guess what's going on. I rather imagine others in the lab can give better suggestions than I could.

5/30/2009 04:40:00 PM  

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