Open AccessAcquisition of chromosome instability is a mechanism to evade oncogene addiction
Author(s) -
Salgueiro Lorena,
Buccitelli Christopher,
Rowald Konstantina,
Somogyi Kalman,
Kandala Sridhar,
Korbel Jan O,
Sotillo Rocio
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910941
Subject(s) - mechanism (biology) , genome instability , chromosome instability , instability , genetics , chromosome , addiction , biology , microbiology and biotechnology , gene , dna , neuroscience , physics , dna damage , quantum mechanics , mechanics
Chromosome instability ( CIN ) has been associated with therapeutic resistance in many cancers. However, whether tumours become genomically unstable as an evolutionary mechanism to overcome the bottleneck exerted by therapy is not clear. Using a CIN model of Kras‐driven breast cancer, we demonstrate that aneuploid tumours acquire genetic modifications that facilitate the development of resistance to targeted therapy faster than euploid tumours. We further show that the few initially chromosomally stable cancers that manage to persist during treatment do so concomitantly with the acquisition of CIN . Whole‐genome sequencing analysis revealed that the most predominant genetic alteration in resistant tumours, originated from either euploid or aneuploid primary tumours, was an amplification on chromosome 6 containing the cM et oncogene. We further show that these tumours are dependent on cM et since its pharmacological inhibition leads to reduced growth and increased cell death. Our results highlight that irrespective of the initial CIN levels, cancer genomes are dynamic and the acquisition of a certain level of CIN , either induced or spontaneous, is a mechanism to circumvent oncogene addiction.