The last decade has witnessed a transformation in the treatment of advanced-stage lung cancer from a largely palliative approach to one where long-term durable remissions and even cures might be within reach. In this review, we discuss the current state of oncogene-directed precision medicine therapies in lung cancer and focus on the major cause of mortality for lung cancer patients: acquired resistance. We consider the multifaceted resistance mechanisms tumors utilize, often simultaneously. We then present areas for future scientific and clinical investigation with an emphasis on population dynamics, early detection, combinatorial therapies targeting resistance mechanisms, and understanding the drug-tolerant persister state.

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