Erlotinib Treatment in Colorectal Cancer Suppresses Autophagy Based on KRAS Mutation

The gene is mutated in approximately 45% of colorectal cancer patients. There are currently very few targeted treatments or therapies equipped to directly inhibit due to its unusual structural intricacies. Erlotinib, an EGFR inhibitor, has previously been demonstrated to reduce cell viability by inducing autophagy in lung cancer cell lines with varying EGFR mutations. In contrast to lung cancer cells, evidence is provided herein for the first time that erlotinib treatment in colorectal cancer (CRC) cell lines reduces autophagy and still results in decreased cell viability. However, the effects of erlotinib in CRC cell lines containing a wildtype gene were different than in cells carrying a mutant gene. We show that there is significantly more downregulation of autophagy in mutant CRC cells compared to wildtype cells, both at transcriptional and translational levels, suggesting that the mutation is advantageous for cancer growth, even in the presence of erlotinib. Cell viability results determined that wildtype CRC cells had significantly more cell death compared to mutant cells. Using patient mRNA datasets, we showed that there was a significant correlation between the presence of the mutation and the expression of autophagy proteins. Additionally, through molecular dynamics simulations, we develop a blueprint for and autophagy protein interaction and the impact of the mutation on autophagy protein regulation. Overall, this is the first report of erlotinib treatment in CRC cells that assesses autophagy, and we demonstrate that autophagy activity is downregulated in these cells. This effect is not only greater in cells carrying a mutation compared to wildtype cells, but the mutant cells also have increased cell viability compared to wildtype cells. We hypothesize that the difference in cell viability and autophagy expression between mutant and wildtype cells after treatment with erlotinib can be of therapeutic value to treat CRC patients carrying mutations.