MEK and PI3K inhibition on pancreatic cancer cells has demonstrated the existence of intrinsic resistance. Therefore, a comprehensive proteome profiling is needed to understand the associated molecular phenotype. PANC-1 and MIA PaCa-2 cancer cells were studied by label-free data-independent acquisition (SWATH) mass spectrometry with extensive peptide fractionation to quantitate and reveal differential expression of several proteins between resistant and sensitive cells. Proteomic differences cover a broad scope of molecular processes and putative candidate proteins for drug response.