Cancer cell plasticity on targeted therapy

Introduction

Novel cancer molecular-targeted therapies allow for significantly prolonging the survival of cancer patients. However, the inevitable acquisition of resistance mechanisms limits the clinical benefit of these treatments. To fully understand how resistance develops, it is crucial to better integrate tumor heterogeneity, cancer cell plasticity, and microenvironment changes by applying cutting-edge single-cell technologies directly on sequentially sampled biopsies from cancer patients.

Targeting Drug-Tolerant Cells

Additionally, to achieve deeper and longer-lasting clinical responses for cancer patients, we will need to target the rare drug-tolerant persister cancer cells. Samples collected before, during, and after treatment will be used to fully describe the characteristics of the cells that are the source of genetic resistant variants that ultimately give rise to tumor relapses.

Methodology

By combining the establishment of patient-derived models, drug screening of epigenetic inhibitors, and transcriptomic and epigenetic characterization of persister cells, we will aim to highlight their vulnerabilities.

Identifying Driver Mechanisms

Finally, identifying the driver mechanisms of genomic evolution by elucidating the link between oncogenic kinases and DNA repair pathways activity will be our innovative strategy to exploit putative susceptibilities to impeach the survival of resistant cells.

Techniques

The use of DNA repair substrates combined with CRISPR gene knockout will aim at confirming the value of targeting DNA repair pathways to profoundly transform the outcome of patients with metastatic cancer.

Conclusion

Overall, by applying new technological breakthroughs at the single-cell level on patient biopsies, digging into the intrinsic nature of persister cells, and taking advantage of DNA repair defects, we will identify innovative treatment strategies to avoid the emergence of resistance in patients.