Development of acquired resistance to the therapeutic effects of an epidermal growth factor (EGFR) tyrosine kinase inhibitor in a patient that is suffering from a cancer is predicted by: (a) obtaining a sample from the patient, wherein the cancer harbors a somatic gain-of-function mutation in the tyrosine kinase domain of EGFR that enhances the sensitivity of the cancer to the tyrosine kinase inhibitor, and (b) testing the sample to determine whether the gene encoding EGFR is present in a mutant form that encodes a T790M mutant of EGFR in addition to the somatic gain of function mutation. A finding that the mutant form is present indicates that the cancer has become or will become resistant to the EGFR tyrosine kinase inhibitor.