In a study published Tuesday in the American Association for Cancer Research’s journal Clinical Cancer Research, researchers identified two novel mutations that cause resistance to alectinib, a drug that belongs to a class of cancer drugs called tyrosine kinase inhibitors. Alectinib is being investigated as a treatment for non-small cell lung cancers (NSCLC) that have alterations in the gene anaplastic lymphoma receptor tyrosine kinase (ALK).
I will get to the part where the researchers dug deeper to understand how alectinib resistance happens, identified drugs that overcame alectinib resistance, and, in that process, formulized new treatment strategies that they used to extend a lung cancer patient’s life. But first, let’s look at the issue of ALK-positive lung cancer drug resistance.
About 3 to 5 percent of all NSCLCs harbor alterations in ALK. Alterations to ALK, such as a fusion with the protein EML4 to form the EML4-ALK fusion oncogene, result in constant activation of the enzyme ALK tyrosine kinase, which causes abnormal downstream signaling leading to cancer. Lung cancers harboring ALK alterations are therefore very sensitive to ALK-targeted tyrosine kinase inhibitors.
However, a major challenge encountered in treating ALK-positive lung cancers with ALK inhibitors is acquired resistance. The Food and Drug Administration-approved ALK inhibitor crizotinib, a first of its kind, is very effective against ALK-positive lung cancers, but almost all patients develop resistance to this drug within a year of treatment. Alectinib, a second-generation ALK inhibitor that was granted Breakthrough Therapy designation by the FDA in 2013, is more potent than crizotinib and overcomes crizotinib resistance. However, as with most molecularly targeted therapies, tumors acquire resistance to alectinib.
In an effort to understand how ALK-positive lung cancers develop resistance to alectinib, Alice T. Shaw, MD, PhD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center, and her colleagues, analyzed a cell line model that is resistant to alectinib treatment, and a tumor sample from an NSCLC patient of Shaw’s, who relapsed on alectinib. They identified two novel mutations—V1180L and I117IT—that confer resistance to alectinib.
To understand how exactly these mutations make the tumors resistant to alectinib, Shaw and colleagues conducted structural analyses using computational simulation. In these experiments, they found that the two mutations decreased the binding affinity of alectinib to its target, the ALK protein.
The next step in their research was to identify next-generation ALK inhibitors able to overcome alectinib resistance caused by the newly identified mutations. From these studies, they found that ceritinib, approved by the FDA in April 2014 for the treatment of ALK-positive NSCLC resistant to crizotinib, can overcome resistance to alectinib. AP26113, an investigational drug currently in clinical trials, was also able to overcome alectinib resistance.
Shaw and colleagues took this knowledge back to the bedside, to a patient whose cancer relapsed on crizotinib first, and then on alectinib. They treated this patient with ceritinib, and this patient had a partial response lasting for seven months.
Another patient with NSCLC, James (Rocky) Lagno, who is benefiting from ceritinib, shares his experience in the AACR Cancer Progress Report 2014. Rocky was diagnosed with lung cancer in 2011, and was told he had about a year to live. When he discovered that his lung cancer was ALK-positive, his oncologist directed him to Shaw, who obtained ceritinib for Rocky on a compassionate use basis. Rocky’s condition has been stable since the middle of 2013.
“It’s a personal choice whether to enter a clinical trial,” Rocky said in the report. “But let’s face it: chemotherapy and radiation have been around for 40 years. You ought to see the new things that modern medicine can do.” Hear more about Rocky’s story in the video below.
“For patients like Rocky, the inevitable question is, ‘What do we do after ceritinib?’” said Shaw in an interview. “Fortunately, our study suggests that you may be able to use another next-generation ALK inhibitor as the next treatment. Depending on the resistance mechanisms the patients’ tumors develop, it may be possible for them to derive clinical benefit from a series of different ALK inhibitors.”
With the advent of tremendous technologies that empower us to analyze and understand cancer as it evolves during treatment, there is hope that cancer may soon become a manageable chronic disease.
To continue to make progress for patients, however, we need more research—and today, the AACR issued a call for ideas for a new Stand Up To Cancer-American Cancer Society Lung Cancer Translational Research Dream Team Grant that will offer up to $20 million in research funding. The grant will fund research projects that have a transformative and synergistic approach to identifying therapeutic interventions for lung cancer and delivering near-term patient benefit.
Cover photo: “2xp2 (human anaplastic lymphoma kinase in complex with crizotinib)” by A2-33 is licensed under CC-BY-SA-3.0 via Wikimedia Commons
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