title: Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells.
abstract: Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases-exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at "just-right" levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Amit Dipak
authors.initials: AD
authors.lastname: Amin
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Soumya S
authors.initials: SS
authors.lastname: Rajan
authors.affiliation: Undergraduate Biology Research Program, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Groysman
authors.affiliation: BIO5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: Praechompoo
authors.initials: P
authors.lastname: Pongtornpipat
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Schatz
keywords: ALK; BRAF; intermittent dosing; oncogene addiction; oncogene overdose; the Goldilocks principle