Researchers at Translational Genomics Research Institute (TGen) and Van Andel Research Institute (VARI) today presented study results in which they conclude that a combination drug therapy may be needed to combat non-small cell lung cancer (NSCLC).
Non-small cell lung carcinoma (NSCLC) is characterized by a remarkable variety of genomic alterations and point mutations. Collectively, these mutations disrupt the normal molecular activity regulating growth and survival of the lung epithelium. However, despite genomic complexity of individual tumors, researchers believe that only a few key mutations are involved in the viability and proliferation of tumor cells.
Crucial role in tumor-call behavior
The study results published online today by the Public Library of Science (PLoS) ONE showed that in NSCLC, the most common form of lung cancer, the STAT3 gene is activated in some NSCLC cell lines by the Janus kinase 2 or JAK2 protein,a human protein that has been implicated in signaling by members of the type II cytokine receptor family (includinginterferon receptors), the GM-CSF receptor family (IL-3R, IL-5R and GM-CSF-R), the gp130 receptor family (e.g. IL-6R), and the single chain receptors.
This signaling can play a crucial role in tumor-cell behavior that may not be effectively inhibited by drugs that selectively target these mutations, the study’s authors concluded. ?This suggests that there may be a potential role for combination therapy, so you have a better chance of knocking out select NSCLC tumors driven by STAT3-JAK2, or keeping it at bay,? said Dr. Glen Weiss, Co-Unit Head of TGen?s Lung Cancer Research Laboratory and Director of Thoracic Oncology at Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, a partnership between TGen and Scottsdale Healthcare that treats cancer patients with promising new drugs.
Inflammatory cytokines can activate STAT proteins via non-receptor tyrosine kinases of the JAK family. Of these, only JAK2 is commonly expressed in cells of the epithelial lineage involved in NSCLC. The JAK2 protein can activate the gene called STAT3, part of a family of genes that provide instructions for making proteins that are part of the essential chemical signaling pathways that control growth and development in cells. STAT3 has been found to be overactive in cases of several types of cancer, including breast, prostate, pancreas, leukemia and lymphoma.
?JAK2-STAT3 signaling plays crucial roles in tumor-cell behavior that may not be effectively inhibited by drugs that selectively target these mutations,? said Dr. Jeff MacKeigan, Head of VARI?s Laboratory of Systems Biology. VARI is TGen?s affiliate in Grand Rapids, Mich.
“The researchers believe that the study results can benefit future lung cancer research because of the study?s clinically annotated tissue microarray,” MacKeigan observed.
For more information:
Looyenga BD, Hutchings D, Cherni I, Kingsley C, Weiss GJ, MacKeigan JP.
STAT3 Is Activated by JAK2 Independent of Key Oncogenic Driver Mutations in Non-Small Cell Lung Carcinoma PLoS ONE Feb 2012 7 (2) e30820.