We have recently identified novel methylation of R198/R200 in EGFR. Our data suggest that Arg‐ methylation may be involved in ligand interaction, receptor dimerization and activation. Thus, we hypothesize that methylation in R198/200 of EGFR may cause resistance to cetuximab. Indeed our data using colorectal cancer cell lines and patient samples strongly support this hypothesis. In the current proposal, we would like to expand our hypothesis in different cancer types including triple negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), and head and neck squamous cell carcinoma (HNSCC), in all of which EGFR plays a critical role. Thus, we propose the following two specific aims. Aim 1: To study the role of the R198/200 methylations on EGFR‐mediated signaling, cellular functions, and drug sensitivity in various types of cancers. Aim 2: To investigate the effect of the R198/200 methylations on tumor progression and their clinicopathologic relevance in various types of cancers.