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.

Integrating genetic dependencies and genomic alterations across pathways and cancer types

“…In contrast, in cell lines without BRAF(A), there is no significant correlation between DUSP4 dependency and MAPK expression (R : 0.03, P = 0.499). These observations are consistent with the Goldilocks principle described in [67], where precise levels of biological factors must be maintained for strong fitness, with either overdose or lack of oncogenic signal resulting in regression of tumor. In this case, DUSP4 inhibition of MAPK1 is most essential in cell lines with hyperactive MAPK signaling due to BRAF(A) alterations.…”

What makes oncogenes mutually exclusive?

“…This concept fits well in the so-called "Goldilocks Principle," the idea that certain biological processes require precise levels in order to promote fitness, where either too little or too much is detrimental. 50 The evidence that ERK signaling obeys this principle was nicely illustrated in a mouse model of breast cancer in which mutant KRAS expression levels were doxycycline-regulated. Low levels of KRAS activity promoted tumor formation, whereas high levels induced growth arrest and senescence.…”

Evolution of Relapse-Proficient Subclones Constrained by Collateral Sensitivity to Oncogene Overdose in Wnt-Driven Mammary Cancer

“…In the clinic, sensitivity to excessive oncogenic signaling likely explains why pharmacologic doses of gonadal hormones paradoxically served as effective treatment for hormone-dependent breast cancers before the advent of modern anti-hormonal drugs ( Haddow et al, 1944 ; Jordan and Ford, 2011 ). More recently, oncogene overdose has been invoked to explain why some cancers, after adapting to potent targeted therapy, paradoxically depend upon continued drug treatment for maintenance and growth ( Amin et al, 2015a , 2015b ; Das Thakur et al, 2013 ; Sun et al, 2014 ). Intriguingly, preclinical models of melanoma, lymphoma, and prostate cancer have led to clinical trials aimed at exploiting oncogene overdose for therapeutic gain in patients ( Amin et al, 2015a ; Schweizer et al, 2015 ).…”

“…More recently, oncogene overdose has been invoked to explain why some cancers, after adapting to potent targeted therapy, paradoxically depend upon continued drug treatment for maintenance and growth ( Amin et al, 2015a , 2015b ; Das Thakur et al, 2013 ; Sun et al, 2014 ). Intriguingly, preclinical models of melanoma, lymphoma, and prostate cancer have led to clinical trials aimed at exploiting oncogene overdose for therapeutic gain in patients ( Amin et al, 2015a ; Schweizer et al, 2015 ). Despite these advances, it remains unclear whether and how oncogene overdose shapes the evolution of incipient RSCs prior to treatment.…”