Understanding molecular mechanisms of Cetuximab insensitivity in Colorectal Cancer (CRC)

Mutational status of KRAS in CRC is used to aid patient stratification for Cetuximab treatment. However, only a subset (10-40%) of patients with wt KRAS respond. We analyzed 40 mCRC tumors for Cetuximab response using a functional ex vivo platform. In the subset of non-responsive tumors, mutational (KRAS/BRAF and PIK3CA) and expression (AREG/EREG) analysis of key genes, transcriptomic profiling and GSEA were carried out to elucidate the molecular mechanisms underlying the response. Our analysis revealed deregulation of multiple pathways, notably Notch and Erbb2 and combined blockade of these two nodes elicited significant antitumor response. These findings collectively indicate the dependence of Cetuximab insensitive mCRC tumors on Notch and Erbb2 for survival and progression. 8 Primary tumors tested in ex vivo platform for response to Cetuximab were subjected to expression analysis