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E. López-Pascual
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-103 - A Goodpasture Antigen-Binding Protein Kinase Inhibitor to Treat Drug-Resistant Metastatic Lung Cancer (ID 1514)
09:30 - 09:30 | Author(s): E. López-Pascual
- Abstract
Background:
Goodpasture antigen-binding protein (GPBP) is a secretable Ser/Thr kinase which regulates the organization of the type IV collagen network in the extracellular matrix. Current evidence suggests that this network interacts directly with Cancer Stem Cells (CSC) and forms a protective shield against anti-tumor therapies. CSC are recognized as responsible for tumor’s drug resistance and invasiveness. Remarkably, expression of COL4A3BP, the gene coding for both GPBP kinase and cytosolic ceramide transporter CERT, has been associated with multidrug resistance and poor prognosis in breast and lung cancer patients. Here, we have developed T12, a highly specific small molecule inhibitor of GPBP kinase and demonstrated its potential to treat drug-resistant and metastatic non-small cell lung cancer.
Methods:
The yeast two-hybrid system was used to identify a five-residue motif responsible for GPBP multimerization and enhanced kinase activity. We then generated a series of peptidomimetic compounds featuring a terphenyl structure. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl] propionic acid, referred to as T12, exhibited a suitable kinase inhibitory activity and toxicokinetics, and as a result was selected for additional testing using relevant ex vivo and in vivo models of human non-small cell lung cancer (A549 and patient-derived primary cultures).
Results:
T12 treatment reduced the viability of human lung cancer cells exhibiting a prevalent mesenchymal-invasive phenotype, but had no effect on human lung cancer cells with a predominant epithelial phenotype. Conversely, the latter responded to T12 when combined with doxorubicin, an inducer of the epithelial-to-mesenchymal transition (EMT). Consequently, we suggest that the GPBP kinase activity and concomitant type IV collagen expression stabilize the privileged niche of the mesenchymal drug-resistant CSC in human lung cancer. Accordingly, down-regulation of either GPBP kinase activity or type IV collagen expression using siRNA or T12 treatment, compromised human lung cancer cell viability only after EMT induction. Moreover, the pivotal role of GPBP in stabilizing the tumor invasive phenotype was further demonstrated by exhibiting reduced tumor implantation and metastasis formation in GPBP [-/-] mice. Finally, confirmation that T12 inhibition of GPBP kinase was responsible for anti-tumor activity in mice was accomplished by showing analogous therapeutic effects following administering of N26, a GPBP-specific monoclonal antibody that inhibits GPBP binding to type IV collagen.
Conclusion:
The general mechanism for multidrug-resistance and poor prognosis associated with COL4A3BP expression depends by and large on its affiliated kinase activity. Thus, T12 emerges as a First-in-Class drug candidate to specifically treat drug-resistant and metastatic non-small cell lung cancer.
