D. Ross Camidge, MD, PhD
Director, Thoracic Oncology Clinical Program, University of Colorado, Denver, CO
Fredika M. Robertson, PhD
Professor, Department of Experimental Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX
D. Ross Camidge, MD, PhD, has served as a principal investigator on numerous national and international clinical trials, including studies that helped pave the way for the approval of crizotinib (Xalkori).
Fredika M. Robertson, PhD, focuses on identifying molecular targets for metastasis. She helped identify dysregulation of anaplastic lymphoma kinase (ALK) signaling in patients with inflammatory breast cancer, in collaboration with Massimo Cristofanilli, MD, chairman of the Department of Medical Oncology at Fox Chase Cancer Center in Philadelphia, and Emanuel F. Petricoin III, PhD, co-director of the Center for Applied Proteomics and Molecular Medicine at George Mason University in Fairfax, Virginia.
What role does the ALK signaling pathway play in normal cells?
ALK is a developmentally regulated kinase that has a proven role in the development of visceral muscle patterning in Drosophila
and in the development of the visual system in mice. Native ALK in adult humans is detectable within the intestine, central nervous system (CNS), and testes, but its function remains largely unknown.Robertson:
The receptor tyrosine kinase ALK is a member of the insulin receptor family and has a role primarily in normal embryonic neural development and differentiation, with limited distribution in adult mammals. The ligands for ALK include midkine and pleiotrophin and, based on a demonstrated role for these ligands in neural development and angiogenesis, ALK has been suggested to play a role in these processes through ALK phosphorylation, associated with activation of PI3K, Akt, and MAP kinase.
How is ALK signaling implicated in the development of cancer?
Activation of ALK in association with neoplasia has been described in two main ways. Most commonly, the 3’ end of the gene containing the kinase domain is fused with the 5’ end of a different gene. The ALK is then expressed as part of a fusion protein, driven by the 5’ gene’s promoter that is active in the cancer tissue. The 5’ fusion partner protein acts as a dimerization motif mediating the activation of ALK.
This mechanism was first identified in some lymphomas but has since been described in subsets of multiple different cancers, often with different 5’ partners, including inflammatory myofibroblastic tumors (IMTs) and non-small cell lung cancer (NSCLC). More rarely, ALK can be activated by a primary mutation occurring in the kinase domain of full-length ALK, examples of which have been described in neuroblastoma and anaplastic thyroid cancer, among other cancers. These same kinase domain mutations and others can also occur as secondary events in cancers activated by ALK
gene rearrangements, but in these situations the mutations are acting as a mechanism of acquired resistance to an ALK inhibitor.Robertson:
ALK is one of the only receptor tyrosine kinases identified to have oncogenic roles in both hematopoietic and solid tumors. ALK
was first discovered based on its fusion with the nucleophosmin gene, designated as NPM-ALK
, which is prevalent in anaplastic lymphoma. Additional fusions of ALK
with other genes have been identified, perhaps most notably with echinoderm microtubuleassociated protein 4 (EML4-ALK), found to be present in a subgroup of patients with NSCLC who are very sensitive to the small-molecule ALK inhibitor crizotinib. The responsiveness of this subgroup of NSCLC patients, who typically have a very poor prognosis, led to the FDA approval of this ALK- targeted therapy, and also to the approval of the tandem EML4-ALK diagnostic assay.