A CINful way to overcome addiction: how chromosomal instability enables cancer to overcome its oncogene addiction

Abstract

Oncogene-addicted tumors present a valuable target for therapeutic intervention and an opportunity to achieve a wide therapeutic window. Nonetheless, resistance to targeted therapies is frequently observed and it arises through multiple mechanisms, including mutations in the target gene. Chromosomal instability, a defining feature of human cancer, has been linked to targeted therapy resistance, but the mechanism underlying this association is poorly understood. In the current issue of EMBO Molecular Medicine, Salgueiro et al show that chromosomal instability can lead to the generation of alternative oncogenic drivers, thereby providing the ability for cancer cells to overcome the oncogene withdrawal bottleneck. Importantly, this study shows that, by generating de novo genomic diversity, chromosomal instability serves as an adaptive response to therapeutic insult.

Figure 1. Chromosomal instability promotes oncogene independence in cancer

(A) Induction of tumors in Kras (K) or Kras/Mad2 (KM) mutant mice resulted in low and high levels of CIN, respectively. (B) Upon doxycycline withdrawal, the majority of tumors regressed, but a minority persisted independent of genotype. Note, the fraction was smaller in K mice. (C) In vitro culture of non‐regressed tumors revealed CIN levels even higher than in primary tumors. In addition, the emergence of an amplification along chromosome 6 containing the oncogene cMet was noted during genomic analyses in non‐regressed but not primary tumors and also validated functionally. (D) In summary, CIN levels were shown to increase following oncogene withdrawal in the absence of doxycycline beyond what was observed in primary tumors and independent of mice's Mad2 genotype.