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May 19, 2022

A Novel Framework for the Next Generation of Precision Oncology Targets

Author Affiliations
  • 1Division of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
JAMA Oncol. 2022;8(7):974-976. doi:10.1001/jamaoncol.2022.0760

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.

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