Fighting Drug Resistance in ALK+ Lung Cancer

Researchers funded by the American Cancer Society and others have made tremendous strides toward improving lung cancer treatment. For example, the discovery of specific genetic mutations that drive certain non-small cell lung cancers (NSCLC) has fueled the development of targeted drugs called tyrosine kinase inhibitors (TKIs).

"When given to a patient with the correct tumor profile, the anti-cancer responses [to TKIs] can be significant and last for many months," says Society researcher Daniel Costa, MD, PhD, associate professor of medicine at Harvard Medical School.

Daniel Costa in lab

However, the benefits don't seem to last in patients with a subtype of NSCLC known as ALK+ lung cancer, which involves a mutation in the ALK (anaplastic lymphoma kinase) gene. There is an "eventual and inescapable resistance that emerges after months to years of therapy," says Costa.

Understanding why and how that happens is a focus of Costa's research. His now-complete Society-funded project, together with separate research efforts at Harvard, is at the forefront of identifying what causes drug resistance in ALK+ and other lung cancers.

“The major reason for studying how drug resistance develops is to provide the framework for the development of the next generation of drugs, ones that can overcome resistance and be given to patients consecutively or in combination,” says William Phelps, PhD, director of the Preclinical and Translational Cancer Research Program at American Cancer Society.

ALK+ lung cancer is of particular concern not only because treatments stop working, but also because it is most often seen in people who have never or rarely smoked. It occurs in about 5% of adenocarcinomas, the most common type of NSCLC.

The FDA approved the first targeted treatments for this aggressive form of cancer just a few years ago. Crizotinib (Xalkori) and ceritinib (Zykadia), called ALK inhibitors or ALK TKIs, are taken by mouth and often prescribed for all stages of the cancer.

Costa's group has studied crizotinib for the treatment of ALK+ lung cancer and found it improves quality of life, disease control, and survival when compared to more traditional chemotherapies. Yet progression eventually occurs in most patients. In the June 2015 Journal of Clinical Oncology, Costa and colleagues reported that crizotinib didn't work as well on lung cancer lesions that spread to distant sites, such as the brain. Earlier research published by his team noted that brain metastasis occurs frequently in patients with ALK+ lung cancer.

"The brain is less exposed to TKIs than the rest of the body due to the blood-brain barrier," he explains. He hopes his ongoing research will result in better therapies to target brain metastasis in patients with ALK+ lung cancer. "Our data points toward the brain as an important, unmet clinical need in the evolving schema for personalized care in lung cancer.”

“The identification of new treatments for all stages of ALK-related and other oncogene-driven lung cancers is a significant priority,” Costa says. He hopes that his research into the mutations involved in such cancers will help usher in a new generation of drugs that not only improve the duration of tumor control, but also may lead to possible cures.

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