Pathway redundancy and feedback loop as drivers of nonresponse in colorectal cancer treatments.

Abstract

e14626 Background: There is urgent need for rational therapy selection based on functional-pathway characterization to achieve significantly improved clinical outcome. Methods: 207 CRC patients were evaluated for >100 signal transduction proteins. Receptor tyrosine kinases (RTKs, i.e. ErbBs, FGFRs, VEGFRs, cMET, IGF1R, etc) and non-RTKs (Src, FAK, etc) as well as Jak/Stat along with AKT and MAPK pathway proteins were analyzed for their level of expression and activation utilizing Collaborative Enzyme Enhanced Reactive (CEER) immunoarray. In addition to pathway profiling, samples were also molecularly characterized for 14 different mutations within the KRAS, BRAF and PIK3CA oncogenes. Results: Both ErbB/VEGFR driven and ErbB/VEGFR-independent signal transduction activation patterns were observed in the CRC patients with complex redundant pathway circuitry. Phosphorylated RTKs led to downstream AKT and MAPK pathway activation. Various mutations in KRAS, PIK3CA and BRAF were found in 42%, 11% and 4% of CRC patients, respectively. KRAS G12D and G13D mutations were the most frequent mutations. Percent of mutant alleles per input DNA increased in matching metastatic tumors when compared to the primary tumors. While downstream signal transduction via AKT and MAPK pathways were similar in both wild-type and mutant tumors, we observed higher levels of potential compensating non-ErbB driven RTK expression/activation in KRAS mutant patients. A significant pathway redundancy was detected in most tumors. Furthermore, pathway diversity in tumors with identical mutational background was evident in this analysis. Conclusions: CEER-based pathway analysis adds value towards understanding of CRC tumor¡&hibar;s potential response under various clinical scenarios. The comprehensive characterization of pathway redundancy allows for rational selection of a combination of targeted agents. A combination of Erbitux with anti-angiogenic therapy may provide most benefit for patients with concomitant EGFR and VEGFR2 activation. Based on pathway circuitry determined by CEER, clinicians can optimize clinical decisions in selecting more effective therapies that target relevant pathway proteins.