KRAS mutation status is being used as the sole
biomarker to predict therapeutic efficacy of
cetuximab in metastatic
colorectal cancer (mCRC). A significant number of mCRC patients with KRAS wild-type (WT)
tumors, however, do not benefit from
cetuximab. We are also lacking efficacy predictors in
head and neck squamous cell carcinomas with an intact KRAS signaling and in
non-small cell lung cancer in which KRAS mutations do not predict
cetuximab efficacy. We recently established pre-clinical models of EGFR gene-amplified KRAS WT A431
squamous carcinoma cells chronically adapted to grow in the presence of
cetuximab. We employed the ingenuity pathway analysis software to functionally interpret data from Agilent's whole human genome arrays in the context of biological processes, networks, and pathways.
Cetuximab-induced activation of the
interferon (IFN)/STAT1 appeared to switch from 'growth inhibitory' in acutely-treated cells to 'pro-survival' in chronically-adapted cells.
Cetuximab treatment appeared to negatively select initially dominant IFN-sensitive clones and promoted selection of IFN- and
cetuximab-refractory
tumor clones constitutively bearing an up-regulated IFN/STAT1 signaling. High-levels of mRNAs coding for the EGFR
ligands amphiregulin (AREG),
epiregulin (EREG), and
neuregulin-1/
heregulin (NRG1) predicted for acute
cetuximab's functioning. Chronic
cetuximab, however, appeared to negatively select initially dominant AREG/EREG/NRG1-positive clones to promote selection of
cetuximab-refractory clones exhibiting a knocked-down
neuregulin signaling. Our current evolutionary mapping of the transcriptomic changes that occur during
cetuximab-induced chronic blockade of EGFR/KRAS WT signaling strongly suggests that mRNAs coding for IFN/STAT1- and EGFR
ligands-related genes can be evaluated as novel predictors of efficacy in KRAS WT squamous
cancer patients being treated with
cetuximab.