Monitoring Metabolic Changes in Response to Chemotherapies in Cancer with Raman Spectroscopy and Metabolomics

Resistance to clinical therapies remains a major barrierin cancermanagement. There is a critical need for rapid and highly sensitivediagnostic tools that enable early prediction of treatment responseto allow accurate clinical decisions. Here, Raman spectroscopy wasemployed to monitor changes in key metabolites as early predictorsof response in KRAS-mutant colorectal cancer (CRC)cells, HCT116, treated with chemotherapies. We show at the singlecell level that HCT116 is resistant to cetuximab (CTX), the first-linetreatment in CRC, but this resistance can be overcome with pre-sensitizationof cells with oxaliplatin (OX). In combination treatment of CTX +OX, sequential delivery of OX followed by CTX rather than simultaneousadministration of drugs was observed to be critical for effectivetherapy. Our results demonstrated that metabolic changes are wellaligned to cellular mechanical changes where Young's modulusdecreased after effective treatment, indicating that both changesin mechanical properties and metabolism in cells are likely responsiblefor cancer proliferation. Raman findings were verified with mass spectrometry(MS) metabolomics, and both platforms showed changes in lipids, nucleicacids, and amino acids as predictors of resistance/response. Finally, key metabolic pathways enriched were identified when cells are resistantto CTX but downregulated with effective treatment. This study highlightsthat drug-induced metabolic changes both at the single cell level(Raman) and ensemble level (MS) have the potential to identify mechanismsof response to clinical cancer therapies.

Automated summary

Resistance to cancer therapies is a significant challenge in cancer management. Rapid and sensitive diagnostic tools are needed to predict treatment response early and make accurate clinical decisions.