Cracking the resistance code: The molecular reclassification of cancer and precision therapy strategies.

The molecular reclassification of cancer has enabled a therapeutic revolution. We now know that metastatic cancers have heterogenous molecular landscapes, which can differ within and between histologies, and may also vary between tumor sites in a single individual, and even between clones in a single tumor. Moreover, clonal evolution develops as cancers metastasize and throughout the course of treatment, which can lead to therapeutic resistance. Treating disease early and personalized therapeutic approaches including molecularly targeted therapies, along with N-of-1 individualized, biomarker-based combination approaches may improve outcomes and address resistance. Reassessing the tumor landscape throughout treatment with frequent tissue biopsies and with liquid biopsies at progression can help identify resistance pathways and provide information for selecting more effective later-line therapies. The heterogenous nature of metastatic tumors at different sites and within a single site can lead to mixed responses; thus, combination therapeutic approaches and understanding the sources of tumor heterogeneity is key to providing durable therapeutic benefit. Elucidating and targeting critical drivers, such as fusions, is also important. In the presence of undruggable key tumor drivers, targeting the immunome, RNA transcripts, and/or cell-surface proteins may circumvent the issue posed by a molecular driver that is not actionable. For tumors with a large number of alterations, exploiting synthetic lethality, precision immunotherapy, functional studies, antibody-drug conjugates, and computational approaches may optimize therapeutic efficacy without targeting every critical driver. Given ongoing clonal evolution and the heterogeneity of metastatic tumors, evolving precision medicine technologies and therapeutic approaches will be critical to improving outcomes for patients with cancer.