Karlsruhe Institute of Technology, January 24th, 2020

Targeting tumor evolution to prevent drug resistance: a new strategy to prolong lung cancer response to EGFR inhibition

L. Grumolato, University of Rouen Normandie, France

Lung cancer is the leading cause of neoplastic-related mortality worldwide. The most common form of this disease, non-small cell lung cancer (NSCLC), is driven, in about 15% of the cases, by an activating mutation of the epidermal growth factor receptor (EGFR). NSCLC patients whose tumors display a mutant EGFR are treated with specific inhibitors of this receptor (EGFRi), such as gefitinib and osimertinib. However, after an initial response, the tumors invariably become resistant to these drugs, as a result of the emergence of subpopulations of resistant cells, which can be already present before the onset of the treatment. We recently devised CRISPR-barcoding, a novel approach to recapitulate and trace the emergence of a new mutation in a subset of cancer cells, thus enabling functional studies of a gene of interest in a context that mimics intratumor heterogeneity. We took advantage of this strategy to identify new compounds capable of preventing amplification of resistant clones from a mass population of NSCLC cells treated with EGFRi. Through a small molecule screen, we identified the multikinase inhibitor sorafenib for its capacity to prevent amplification of resistant cells in combination with EGFRi. We showed that sorafenib can prevent the emergence of clones displaying different mechanisms of resistance to EGFRi, including secondary EGFR mutations, overexpression of other receptor tyrosine kinases, such as MET and HER2, or aberrant activation of downstream effectors of the EGFR signaling, including KRAS, PIK3CA and BRAF. These results were confirmed in vivo, using a CRISPR-barcoding xenograft model of NSCLC resistance to EGFRi. Our data indicate that, in combination with an EGFRi, sorafenib preferentially targets resistant cells, resulting in an overall inhibition of therapy-induced tumor evolution. Mechanistically, we showed that the effects of sorafenib in NSCLC cells are independent of the MAPK pathway, and rely instead on the early inhibition of eIF4E and STAT3 phosphorylation, and the later downregulation of MCL1 and EGFR. Together, our results indicate that, by interfering with the positive selection of resistant clones, a co-treatment with sorafenib could substantially prolong NSCLC response to EGFR inhibition.

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