Martin Sos - A 11

Genomic and molecular characterization of the evolutionary process of drug resistance in EGFR-mutant lung cancer

Abstract

Despite a dramatic paradigm shift in the genomic classification of lung tumors and the advent of precision medicine, the efficacy of current therapies for advanced stage lung cancer patients remains largely disappointing. This is not too surprising considering the genomic complexity of cancer and the dynamic evolution of unique cell clones that contribute to the heterogeneity of individual tumors. Here, we propose to characterize the genomic and molecular dynamics of clonal evolution in EGFR-driven lung tumors and their implication for therapeutic response to targeted drugs. The plan is tailored to achieve two major goals:

  1. Systematically characterize the genomic and transcriptomic architecture of EGFR-mutant tumors.
  2. Functionally link the evolution of EGFR-driven lung tumors with their vulnerability to targeted drugs.


To achieve these aims, we will apply genome as well as transcriptome sequencing and implement modeling of the subclones in the individual biopsy. In parallel, we will employ complementary in vitro models including well as patient-derived cell lines to assess the impact of the molecular architecture on tumor formation and response to targeted drugs in EGFR-mutant lung cancer. Finally, we will explore a genomic framework to predict the clonal evolution of druggable resistance mechanisms that may arise in EGFR-mutant tumors. We anticipate that our results might help understand how the genomic and transcriptomic architecture may influence tumor development and the response of lung cancer patients to precision medicine.

Clinical/medical relevance and sustainability in disease understanding

Lung cancer still represents the most frequent cancer killer worldwide. The development of drugs that inhibit mutant EGFR in lung adenocarcinoma has dramatically prolonged the overall survival of these patients. However, the development of resistance remains inevitable. Here, we will study the molecular drivers that shape the evolutionary process of resistance to uncover clinically tractable targets in order to prevent recurrence of disease in these patients.


Prof. Dr. med. Martin Sos

Institute for Pathology

Prof. Dr. med. Martin Sos

Principal Investigator A 11

martin.sos@uni-koeln.de

Work +49 221 478 98771

Institute for Pathology
Weyertal 115b
50931 Cologne

Publications - Martin Sos

Link to PubMed