One of the significant barriers for effective anti-cancer therapy is emergence of drug resistance. In almost all cases, acquired resistance and relapse often follow an initial effective response to a targeted therapeutic agent. Understanding molecular mechanisms that confer resistance is vital to develop novel therapies to achieve durable response. Kinase inhibitors are some of the widely used targeted therapeutic agents to treat several cancers. In this study, we investigated mechanisms associated with erlotinib resistance in head and neck squamous cell carcinoma (HNSCC) and vemurafenib/dabrafenib resistance in melanoma. To investigate resistance mechanisms, drug resistance clones of HNSCC cell line and melanoma cell lines were derived by subjecting them to selection pressure under chronic drug treatment. Exome sequencing was carried out to identify mutations and copy number alterations associated with resistance clones. Global proteomic and phosphoproteomic profiling was carried out to identify altered signaling mechanisms associated with drug resistant clones. Our data revealed several genomic alterations and proteomic changes associated with erlotinib resistant cells in HNSCC. Integrated analysis of genomic and proteomic data showed activation of MAP kinase pathway as a potential mechanism of erlotinib resistance in HNSCC. Growth inhibition studies using MAP2K1 inhibitor showed potent activity against erlotinib resistant cells. We observed cMET amplification and pathway activation in BRAF inhibitor resistant melanoma cells. MAP2K1 inhibition might be a useful strategy to overcome erlotinib resistance in HNSCC. Similarly, targeting cMET might be beneficial in overcoming BRAF inhibitor resistance in melanoma. Our study demonstrates advantages of integrating genomic and proteomic data to characterize drug resistance mechanisms in cancers.