Resistance to targeted therapies like tyrosine kinase inhibitors, is a major impediment to cures for various human cancers. Accumulating evidence suggests oncogene amplification as a critical mechanism for acquired resistance. However, oncogenes can be amplified in various forms and the amplified oncogenes vary from patient to patient, which presents a challenge to develop new therapeutic targets. Our unpublished research has discovered a novel mechanism for controlling oncogene amplification. We are developing PROTAC-based small molecules to target key regulatory factors. We will initially focus on metastatic lung cancer, then expand to other tumor types, such as glioma, breast cancer, and melanoma.