Abstract
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 cMet oncogene. We further show that these tumours are dependent on cMet 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.
Highlights
Chromosome instability (CIN) is a widespread phenomenon in malignancies characterized by the inability of a cell to maintain its diploid chromosome number, leading to a state of aneuploidy
We present results that mechanistically demonstrate how, in the context of breast tumorigenesis and oncogene withdrawal, CIN allows tumour cell populations to evolve past their dependence on their initiating oncogene via the production of oncogenic somatic copy number alterations (SCNAs) (e.g. Met amplification)
Sequencing data from resistant tumours showed that the percentage of genomic alterations per chromosome was higher in KrasG12D/ Mad2 (KM) non-regressed tumours, the total number of SCNAs in K and KM was similar (Figs 2 and EV1)
Summary
Chromosome instability (CIN) is a widespread phenomenon in malignancies characterized by the inability of a cell to maintain its diploid chromosome number, leading to a state of aneuploidy. Though CIN is often reported to cause whole or partial chromosome changes, it is known to cause smaller focal somatic copy number alterations (SCNAs) including amplifications and deletions (Janssen et al, 2011; Burrell et al, 2013). Many SCNAs are clearly pro-tumorigenic (e.g. lower expression of TP53 via whole chromosome loss or focal amplification of KRAS), the majority are thought to be detrimental to the cell (Sansregret & Swanton, 2017). High levels of CIN and high rates of SCNA generation may lead to imbalanced expression of proteins encoded on the affected DNA regions, endangering the survival of a tumour’s lineage. It is becoming clear that an optimal level of CIN can be achieved that is tolerated by tumour cells while promoting diversification of subclones and facilitating adaptation to selective pressures (e.g. drug treatment) during tumour development (Rowald et al, 2016)
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