Outsmarting Cancer’s Survival Skills

By Esther Napolitano,

Thursday, April 9, 2015

MSK investigators Joan Massagué and Anna Obenauf
Summary

Most cancers treated with targeted therapy ultimately become resistant to treatment, stop shrinking, and eventually progress. New research led by investigators at Memorial Sloan Kettering shows how melanoma and lung cancer cells that initially respond to targeted therapies develop drug resistance. The study also identifies potential treatment strategies that may delay or prevent tumor relapse in people with these types of cancer.

Highlights
  • Personalized medicine targets specific genetic errors that fuel cancer.
  • Most tumors shrink but eventually learn to resist therapy and relapse.
  • Targeted drugs cause some cancer cells to develop defense mechanisms.
  • These mechanisms protect the cells against targeted therapy.
  • Disabling the cell’s defenses may prevent drug resistance and relapse.

The development of targeted therapies is a major leap forward in the treatment of solid tumors. Unfortunately, the curative effects of these personalized approaches — which are selected based on the biology of an individual’s tumor — are usually temporary. The vast majority of cancers treated with targeted therapy ultimately become resistant to treatment, stop shrinking, and eventually progress.

New research led by investigators at Memorial Sloan Kettering and recently published in the journal Nature gives insight into how melanoma and lung cancer cells that initially respond to targeted therapy develop drug resistance. The study also identifies potential treatment strategies that may delay or prevent tumor relapse in people with these types of cancer.

Understanding the Nature of the Enemy

For years, researchers have puzzled over the mechanisms that allow cancer cells to evade targeted therapies and continue to grow. Previous studies have identified individual factors that can diminish the impact of a therapy. However, efforts to target those single mechanisms and disable their function have only marginally improved the long-term effectiveness of targeted treatments.

“Our study found that it’s not just one factor but a complex network of mechanisms that are involved in defending the tumor cells against the effects of targeted therapy,” says the study’s lead investigator, Anna Obenauf, a research associate in MSK’s Cancer Biology and Genetics Program. “These mechanisms are responsible for the patient’s ultimate relapse. We’ve shown how previously identified factors work together to stimulate the growth and spread of small subpopulations of tumor cells that are inherently resistant to treatment.”

Now we know the nature of the enemy, and it's putting out all that it's got.
Joan Massagué

How does this happen?

“The treated tumor cells release a storm of signals that produces growth factors and activates as many genes as possible,” explains Joan Massagué, Director of the Sloan Kettering Institute and senior author of the study. “The signals mount an all-out response to shield these drug-resistant tumor cells from pharmacologic attack and aggressively promote their survival and metastasis, or spread. Now we know the nature of the enemy, and it’s putting out all that it’s got.”

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Combining Treatments to Outwit Cancer’s Survival Skills

Using mouse models that were treated with a targeted therapy called vemurafenib, researchers added a drug that inhibits the specific cell process — called the PI3K/AKT/mTOR pathway — that is activated by the network of signals involved in helping melanoma and lung cancer cells survive the effects of targeted therapy. This strategy blunted the growth of drug-resistant cancer cells, suggesting that a similar combination of targeted therapies may potentially delay or prevent tumor relapse in patients.

“Based on these results, we think that longer-lasting tumor regression may be possible with a combination of treatments that inhibits the genetic abnormalities that drive cancer growth and also targets the common pathway through which some tumor cells act to promote drug resistance and to survive,” notes Dr. Obenauf.

Longer-lasting tumor regression may be possible with a combination of treatments.
Anna Obenauf

“We need to pursue clinical trials that evaluate this and other combinations of treatment approaches,” adds Dr. Massagué , who notes that immunotherapy may be an optimal complement to targeted therapy because it’s based on boosting the immune system’s inherent ability to fight cancer. “It’s worth exploring a completely different and innovative approach like immunotherapy, which may be able to finish off the job that the other targeted drugs cannot fully do on their own.”

Additional study investigators from MSK include Neal Rosen — a long-standing leader in research focused on determining mechanisms that contribute to drug resistance. Researchers from the University of Cambridge, in England; the University of California, Los Angeles; and Yale University School of Medicine, New Haven, also contributed to this study.

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The work was supported by grants from the American Association for Cancer Research (Stand Up 2 Cancer); the MSK Metastasis Research Center; the National Institutes of Health (grants CA163167 and CA129243); the Congressionally Directed Medical Research Program of the Department of Defense; the Howard Hughes Medical Institute; and the Cancer Center Support Grant P30 CA008748.

Comments

There could be two reasons for the release of resistant/protective signaling molecules by the "tumor cells". (a) According to Lamarckian theory the tumor cells are co-evolving with the drug and spew out chemicals as the goal of nature is "survival". However adaptability takes over generations so this points to the possibility that there could be a pre-existing set of resistant cells , the so called cancer stem cells or cells exhibiting stemness potential, which could be selected by the drug-the "darwinian law of natural selection". In this case these "selected cells" spew out drug resistant molecules. In either case one has to deliver testfiable experiments i.e take a drug sensitive cell line, keep on adding drug , select for drug resistant clones (compare genome/methylome)of emergent resistant clones to original sensitive cells-lammarckian theory is proved. However if natural selection is the order of the day then the selection involves selection of a few cells/resistant clones out of the entire pool, while lamarck predicts the entire population should adapt to the new drug. this is related to the hierarchical versus stochastic model of putative "cancer stem cells". It is a numbers game. darwin predicts fewer numbers which are "selected" and follow a hierarchical model of evolution. Lamarck predicts larger adaptable numbers which follow stochastic evolution. My best bet is it is a combination of both functioning as a serial as well as a parallel processor.

I think the dose of the drug will determine if an adaptive response occurs.

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