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Leukemias with ALK mutations identified, may respond to ALK inhibitors

Mutations in the ALK gene were identified in the tumors of two leukemia patients, and laboratory studies indicated that leukemias harboring these mutations may respond to ALK inhibitors such as crizotinib and ceritinib, according to a study published in Cancer Research that was conducted by researchers with the Knight Cancer Institute at Oregon Health & Science University. Cancer Research is a journal of the American Association for Cancer Research.

"Genetic lesions involving ALK have been seen recurrently in a number of different types of solid tumors, but to my knowledge, ALK mutations have not previously been implicated as a major contributor to leukemia," said Jeffrey Tyner, Ph.D., a top researcher with the OHSU Knight Cancer Institute and assistant professor of cell, developmental and cancer biology in the OHSU School of Medicine. "The discovery of new mutant versions of ALK that may contribute to the development of leukemia and can be therapeutically targeted suggests new treatment options for patients with leukemia with ALK mutations."

Genome-sequencing technologies have dramatically increased the amount of genetic information that can be collected from a patient's tumor; however, a lot of this genetic information is not yet clinically actionable due to our lack of knowledge regarding the relevance of many of the mutant genes, explained Tyner. Understanding which mutant genes are important in the disease process, so that they can be paired with targeted therapies, is an important step, he said.

Tyner and colleagues performed deep sequencing of 1,862 kinase and kinase- associated genes in 185 tumor samples, which included samples from 96 patients with acute myeloid leukemia, 51 with acute lymphoblastic leukemia, and 38 with myeloproliferative neoplasms. Of these, two samples, one from a pediatric patient with B-cell ALL and one from an adult patient with AML, had one ALK mutation each.

To assess whether the two mutations identified had the potential to make a cell cancerous, the researchers introduced the mutations into laboratory- grown leukemia cells that normally depend on an external growth factor for growth and survival and found that the mutations allowed these cells to grow even in the absence of an external growth factor, indicating that these mutations were capable of driving abnormal cell growth.

Further laboratory studies indicated that leukemia cells harboring either of the two mutations could be inhibited by several ALK inhibitors, including crizotinib and ceritinib, two therapeutics approved by the Food and Drug Administration for the treatment of ALK-positive metastatic non-small cell lung cancer.

"These findings suggest that broader use of ALK inhibitors should be considered and that these drugs could be applied on the basis of genetic features of a patient's tumor cells," said the study's first author, Julia Maxson, Ph.D., who conducted this research at the OHSU Knight Cancer Institute. Maxson is presently a postdoctoral fellow in the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle.

This study was funded by the Howard Hughes Medical Institute, National Cancer Institute grants (K99 CA190605-01, 4 R00CA151457-03 and 1R01CA183974-01), the Leukemia & Lymphoma Society, a Medical Research Foundations Early Clinical Investigator Award, the St. Baldrick's Foundation, the V Foundation for Cancer Research and the Gabrielle's Angel Foundation for Cancer Research.

In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regard to this research project, Tyner and Maxson declare no conflicts of interest. Review details of OHSU's conflict of interest program to find out more about how we manage these business relationships.


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