Biomarker discovery involves identifying genetic abnormalities within a tumor. However, one of the main challenges in defining such therapeutic targets is accounting for the molecular heterogeneity of cancer. By integrating somatic mutation and gene expression data from hundreds of heterogeneous cell lines from the Cancer Cell Line Encyclopedia (CCLE), we identify sequences of genetic events that may help explain common patterns of oncogenesis across 22 tumor types, and evaluate the general effect of late-stage mutations on drug sensitivity and resistance mechanisms. Through gene enrichment analysis, we find several cancer-specific and immune pathways that are significantly enriched in each of our three proposed phases of cancer progression. By further analyzing the drug activity area associated with compounds that target the BRAF oncogene, a known predictor of drug sensitivity for several compounds used in cancer treatment, we verify that the acquisition of new driver mutations interferes with the targeted drug mechanism, meaning that cells without late-stage mutations generally respond better to drugs.