Abstract
Preclinical cellular response profiling of tumor models has become a cornerstone in the development of novel cancer therapeutics. As efforts to predict clinical efficacy using cohorts of in vitro tumor models have been successful, expansive panels of tumor-derived cell lines can recapitulate an "all comers" efficacy trial, thereby identifying which tumors are most likely to benefit from treatment. The response profile of a therapy is most often studied in isolation; however, drug treatment effect patterns in tumor models across a diverse panel of compounds can help determine the value of unique molecular target classes in specific tumor cohorts. To this end, a panel of 19 compounds was evaluated against a diverse group of cancer cell lines (n = 311). The primary oncogenic targets were a key determinant of concentration-dependent proliferation response, as a total of five of six, four of four, and five of five phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, insulin-like growth factor-I receptor (IGF-IR), and mitotic inhibitors, respectively, clustered with others of that common target class. In addition, molecular target class was correlated with increased responsiveness in certain histologies. A cohort of PI3K/AKT/mTOR inhibitors was more efficacious in breast cancers compared with other tumor types, whereas IGF-IR inhibitors more selectively inhibited growth in colon cancer lines. Finally, specific phenotypes play an important role in cellular response profiles. For example, luminal breast cancer cells (nine of nine; 100%) segregated from basal cells (six of seven; 86%). The convergence of a common cellular response profile for different molecules targeting the same oncogenic pathway substantiates a rational clinical path for patient populations most likely to benefit from treatment. Cancer Res; 70(9); 3677-86. (c)2010 AACR.
Highlights
The expanding development and use of targeted therapies for cancer treatment reflects an increasing understanding of key oncogenic pathways and how the targeted perturbation of these pathways corresponds to clinical response
Human cancer cell line screening panel A total of 311 unique cancer cell lines were purchased from several vendors (American Type Culture Collection; Developmental Therapeutics Program, National Cancer Institute; German Resource Centre for Biological Material; and European Collection of Animal Cell Cultures) and grown to standard culture media recommended by the vendor (Supplementary Table S2)
Some, but not all, cell lines that respond to phosphatidylinositol 3-kinase (PI3K)/AKT inhibition do not respond to upstream inhibition of the ERBB1/2 receptor tyrosine kinases (RTK)
Summary
The expanding development and use of targeted therapies for cancer treatment reflects an increasing understanding of key oncogenic pathways and how the targeted perturbation of these pathways corresponds to clinical response. The overall degree of correlation between compounds of similar target classes is, in part, likely a manifestation of the variable levels of growth and survival dependence each cell line has on the activation of different oncogenic pathways.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
