PI3K Inhibition May Fuel Cancer Rather Than Fight It

Dario C. Altieri, MD

Dario C. Altieri, MD

A study, by M. Cecilia Cano, PhD, et al at the Wistar Institute, Philadelphia, has shown that monotherapy treatment with phosphatidylinositol-3 kinase (PI3K) inhibitors may worsen a patient’s cancer by causing more aggressive tumor cell behavior and increasing the likelihood of metastases to other organs.^1,2According to these findings, published inProceedings of the National Academy of Sciences,¹PI3K inhibitors appear to reprogram tumor cell mitochondria and move them to positions that promote the spread of disease.

PI3K inhibitors function by impeding one or more of the PI3K enzymes of the PI3K/AKT/mTOR pathway—an important signaling pathway for many cellular functions, including growth control, metabolism, survival, and proliferation.^3-5This pathway contains numerous components, the inhibition of which may result in tumor suppression.^3,5Therefore, PI3K has been deemed a master switch by many cancer researchers²and has become the focus of extensive research on therapies aimed at targeting every aspect of the pathway.^4,5

Despite the initial promise of these medicines, PI3K inhibitors have produced only modest short-term benefits, perhaps due to drug resistance.^2,6Drug resistance is a key barrier in achieving long-term remission, or even cures, and considerable effort is being devoted to better understanding how tumors adapt to therapy, how tumors maintain metastatic potential, and how they continue growing.²Some tumors may adaptively reprogram their signaling pathways to evade therapy-induced stress, in turn acquiring more aggressive disease traits.⁶

In an interview withTargeted Oncology,Dario C. Altieri, MD, president and CEO of the Wistar Institute and the lead study investigator, stated that small-molecule inhibitors of PI3K should not be used as monotherapy. “Our research has shown that tumors quickly adapt to this regimen and acquire traits of a more aggressive and potentially invasive disease,” he said. However, these agents may be beneficial for combination regimens.⁵

Study Objective

Altieri et al focused on the role of the mitochondrion, which is the portion of the cell responsible for energy production. Specifically, the researchers sought to discern how mitochondria become reprogrammed when exposed to PI3K inhibition and how these energy sources may prevent the effectiveness of targeted agents from reaching expectations.²

Unexpected Findings

PI3K inhibition caused mitochondria to migrate to the peripheral cytoskeleton of the tumor cells, whereas the mitochondria of untreated cells were seen clustered around the cell nucleus. PI3K inhibition diverted the mitochondria to specialized regions of the cell membrane that are implicated in cell motility, and thus, the cells could move spontaneously, permitting invasion.²

Earlier work by Altieri et al confirmed that tumor cells rely on the energy produced by mitochondria more significantly than previously thought; however, “What we have shown in this [new] study is that, in somewhat of a paradox, treatment with a PI3K inhibitor causes a tumor cell’s mitochondria to produce energy in a localized manner, promoting a far more aggressive and invasive phenotype,” Altieri said.²Therefore, he feels that this treatment appears to be “doing the opposite of its intended effect.”²Regardless, Altieri noted, “These findings continue to support the idea that the mitochondria of tumor cells are crucial to tumor survival and proliferation. It’s certainly counterintuitive that a drug designed to fight cancer may in actuality help it spread, but by identifying why this is happening, we can develop better strategies that allow these drugs to treat tumors the way they should.”²

These findings emphasize the need for greater understanding of how molecular therapy may affect tumor behavior, according to Altieri. “Mechanisms of cellular adaptation like the one described in our study may be directly responsible for treatment failure [observed] in the clinic.”

A Silver Lining

Altieri affirmed that mitochondrial function plays a key role in the adaptation of tumors to PI3K therapy. In turn, “this promotes a more invasive phenotype,” he said, which leads to new research opportunities. “It is now feasible to target mitochondria for cancer therapy, and we envision new studies to focus on rational combination strategies to interfere with mitochondrial adaptation together with PI3K inhibition,” he stated. Altieri and his team have shown that targeting mitochondrial functions for tumor therapy is feasible, and it could eventually represent a novel therapeutic strategy.^2,6

References

1. Caino MC, Ghosh JC, Chae YC, et al. PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion.Proc Natl Acad Sci USA.2015; Jun 29. doi: 10.1073/pnas.1500722112.
2. The Wistar Institute. Despite being designed to treat cancer, this class of drugs appears to reprogram the mitochondria of tumor cells and move them to “strategic” positions for invasion [press release]. http://www.newswise.com/articles/view/636357/?sc=sphr&xy=10013055. Accessed July 2, 2015.
3. Kurtz JE, Ray-Coquard I. PI3 kinase inhibitors in the clinic: an update.Anticancer Res.2012;32(7):2463-2470.
4. Akinleye A, Avvaru P, Furqan M, Song Y, Liu D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics.J Hematol Oncol.2013;6(1):88. doi: 10.1186/1756-8722-6-88.
5. American Society of Clinical Oncology. Exploring the pathway: the PI3K pathway fact sheet. 2015; May 31. http:// https://am.asco.org/exploring-pathway-pi3k-pathway-fact-sheet. Accessed July 2, 2015.
6. Proceedings of the National Academy of Sciences of the United States of America. PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion [Significance]. http://www.pnas.org/content/early/2015/06/23/1500722112.abstract. Accessed July 2, 2015.