20: Multi-omic Analysis Reveals Potential Mechanisms of EGFR-inhibitor Resistance in Right Sided Colon Cancer Liver Metastases

Introduction: There is growing interest in the biological differences between right and left sided colorectal cancer (RCC, LCC), in an attempt to understand what underpins their differing clinical trajectories and behaviors, particularly in metastatic disease, including RCC resistance to EGFR-inhibitors (EGFR-i).


Methods: To continue probing these differences, untargeted metabolomics was performed using liquid chromatography mass spectrometry (LC-MS) on patient-matched liver metastases (LM) and normal liver (NL) intraoperatively frozen tissue samples from colorectal cancer patients (RCC: n=32; LCC: n=58). The relative abundances of metabolites between RCC and LCC LM, normalized for background NL, were compared via a novel metric, the R-L (Right-Left) Index.


Results: Among the most differentially abundant metabolites, there were several indicative of increased reactive oxygen species (ROS) in RCC LM relative to LCC LM; notably, reduced-glutathione (GSH), one of the main antioxidants in cells, was among the most substantially and significantly decreased (R-L index < -1.96) (p = 0.03). Furthermore, though they did not reach statistical significance, dehydroascorbic acid (DHA) (p=0.22), cysteine-s-sulfate (Cys-SSO3H) (p=0.12), and Glycochenodeoxycholic acid (GCDCA) (p=0.09), all linked to increased ROS, were among the most substantially increased (R-L index > 1.96). To further probe these findings, an independent transcriptomic dataset containing data from RCC LM (n=44) and LCC LM (n=139) was reanalyzed, demonstrating a strong downregulation of STC1 in RCC LM versus LCC LM, as the top differentially expressed gene (q=3.34E-05; log2FC=-2.35).


Conclusions: These findings represent two possible mechanisms for EGFR-i resistance in RCC LM: 1) The glycoprotein STC-1 is a known inhibitor of MEK-ERK1/2 signaling – a key downstream effector of EGFR, and implicated in EGFR-i resistance. MEK-ERK1/2 signaling is in turn activated by ROS. 2) ROS inhibit PTP1B, an important direct inhibitor of EGFR. Taken together, the results suggest EGFR itself may be activated in RCC LM, counteracting is inhibition, as well as bypassed, via downstream MEK signaling activation.