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Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Acquisition of chromosome instability is a mechanism to evade oncogene addiction
Lorena Salgueiro1, Christopher Buccitelli2, Konstantina Rowald1
1Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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.
Insights
Tumors evolve chromosome instability (CIN) to resist targeted therapies. This genomic instability, particularly aneuploidy, accelerates resistance by enabling genetic changes like cMet amplification, crucial for cancer survival.
Area of Science:
- Oncology
- Genomics
- Cancer Evolution
Background:
- Chromosome instability (CIN) is linked to cancer therapeutic resistance.
- The role of CIN as an evolutionary mechanism to overcome therapy-induced bottlenecks remains unclear.
Purpose of the Study:
- To investigate if tumors acquire genomic instability as an adaptive strategy against targeted therapy.
- To determine the role of CIN in the development of resistance in Kras-driven breast cancer.
Main Methods:
- Utilized a Kras-driven breast cancer model to study chromosome instability (CIN) and aneuploidy.
- Performed whole-genome sequencing on resistant tumors.
- Investigated the effect of cMet inhibition on resistant tumor growth and survival.
Main Results:
- Aneuploid tumors developed resistance to targeted therapy more rapidly than euploid tumors.
- Persisting chromosomally stable cancers acquired CIN during treatment.
- Amplification of the cMet oncogene on chromosome 6 was the predominant alteration in resistant tumors, regardless of initial CIN levels.
- Pharmacological inhibition of cMet reduced growth and increased cell death in resistant tumors.
Conclusions:
- Cancer genomes are dynamic, with CIN acquisition being a key mechanism for circumventing oncogene addiction.
- Both initially aneuploid and euploid tumors can develop resistance through CIN, often involving cMet amplification.
- Targeting cMet presents a potential therapeutic strategy for overcoming resistance in CIN-associated cancers.
