Actionable Oncogenic Drivers (ROS1, MET, RET, NTRK, BRAF, HER2, KRAS)

This entry represents a composite group of seven distinct actionable oncogenic drivers that are critical in precision oncology, particularly for non-small cell lung cancer (NSCLC) and other solid tumors [15]. The group includes receptor tyrosine kinases such as Proto-oncogene tyrosine-protein kinase ROS1 [1], Hepatocyte growth factor receptor (MET) [2], Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [3], the Neurotrophic receptor tyrosine kinase (NTRK) family [4], and Receptor tyrosine-protein kinase erbB-2 (HER2) [6]. It also includes the downstream B-Raf proto-oncogene serine/threonine kinase (BRAF) [5] and the membrane-associated GTPase KRas [7]. These proteins normally regulate essential cellular processes like growth, differentiation, and survival through the MAPK/ERK and PI3K/AKT signaling pathways [16]. In various cancers, these genes undergo somatic alterations—such as point mutations (BRAF V600E, KRAS G12C), gene fusions (ROS1, RET, NTRK), or amplifications/skipping mutations (MET, HER2)—that lead to constitutive, ligand-independent signaling [17]. This aberrant activity drives malignant transformation and tumor progression. Therapeutic strategies targeting these drivers have revolutionized treatment, moving from broad-spectrum chemotherapy to highly specific small-molecule inhibitors (e.g., Sotorasib for KRAS, Selpercatinib for RET) and monoclonal antibodies or conjugates (e.g., Trastuzumab deruxtecan for HER2) [8-14]. Identifying these specific alterations through molecular profiling is now standard of care to guide the selection of matched targeted therapies [15].

Other names

Actionable mutationsOncogenic kinase driversNSCLC biomarker panelTargetable genomic alterations

Inhibition of kinase catalytic activity via ATP-competitive binding, allosteric inhibition of GTPase signaling, or antibody-drug conjugate mediated cytotoxicity.