In the 2 decades since the US Food and Drug Administration (FDA) approval of imatinib for treatment of chronic myeloid leukemia, the paradigm of biomarker-guided therapeutics has produced major clinical breakthroughs for subsets of patients with cancer. This remarkable progress has been largely fueled by development of therapeutics against what we term first-order targets, or molecular signaling nodes that drive a cellular pathway essential for cancer survival and proliferation. These are typically kinases abnormally activated via gain-of-function genetic alterations present in founding tumor cells, leading to their universal presence within a cancer population. While cellular plasticity or compound genetic alterations can still abrogate therapeutic efficacy, monotherapy inhibition of a first-order target can lead to frequent and profound clinical responses. Notable examples include the clinical success of anaplastic lymphoma kinase inhibitors against anaplastic lymphoma kinase fusion–positive non–small cell lung cancer.
Chen CT, Ford JM. A Novel Framework for the Next Generation of Precision Oncology Targets. JAMA Oncol. 2022;8(7):974–976. doi:10.1001/jamaoncol.2022.0760
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