The role of integrins as a determinant of drug response and resistance
AuthorDamiano, Jason Sinclair
AdvisorDalton, William S.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractDrug resistance continues to be one of the major obstacles to the successful treatment of hematopoietic cancers. Historically, most of the research being done in this area has been focused on reversing mechanisms of resistance which are known to be acquired by the tumor cell in vitro. Fewer studies have attempted to determine what intrinsic mechanisms allow these cells to resist the apoptosis inducing effects of cytotoxic drugs in an in vivo setting. It is now known that a tumor cell's interactions with its microenvironment can have a major influence on whether it lives or dies. The research presented in this dissertation shows that tumor cell interactions with the extracellular matrix component fibronectin influence cell survival following cytotoxic drug exposure, a phenomenon which has been termed Cell Adhesion Mediated Drug Resistance (CAM-DR). In the 8226 myeloma cell line, p130Cas is activated by Src following fibronectin (FN) adhesion, but this signaling pathway did not have an immediate effect on drug response. Similarly, members of the MAPK family, including ERK1/2 and p38, were found to be inactivated by FN adhesion but not to play a short-term role in suppressing drug induced apoptosis. Furthermore, experiments utilizing the K562 CML cell line demonstrated that cytoprotective signaling by the integrins is independent of AKT and BCR/ABL-associated signaling. By allowing the malignant cell to avoid cytotoxic drug induced apoptosis, the integrins may play a significant role in the generation of tumors which are refractory to chemotherapy. Pharmacological agents targeted at these adhesion molecules or at downstream signaling partners have the potential to potentiate the actions of anti-tumor agents and improve clinical responses.
Degree ProgramGraduate College
Pharmacology and Toxicology