Cancer cell plasticity on targeted therapy

Novel cancer molecular-targeted therapies allow to significantly prolong 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. 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. By combining the establishment of patient-derived models, drug-screening of epigenetic inhibitors, transcriptomic and epigenetic characterization of persister cells we will aim to highlight their vulnerabilities. Finally, identify 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. The use of DNA repair substrate 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. Overall, by applying new technological breakthrough at the single cell level on patient biopsies, digging into the intrinsic nature of persister cells and taking advantages of DNA repair defects we will identify innovative treatment strategies to avoid the emergence of resistance in patients.