Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells

Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Here we show that the lack of sensitivity of these cells to EGFR-TKIs constitutes a vulnerability that can be potentially targeted. Through a DNA barcoding approach, we demonstrate that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells, thus resulting in overall inhibition of clonal evolution within the tumor cell mass population. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK interacting kinase (MNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR. Using several xenograft and allograft models to recapitulate different mechanisms and kinetics of acquired resistance, we show that the sorafenib-EGFR-TKI combination can substantially delay tumor growth and promote the recruitment of inflammatory cells. Together, our findings indicate that sorafenib can substantially prolong the response to EGFR-TKIs by targeting NSCLC capacity to adapt to treatment through the emergence of resistant cells. ### Competing Interest Statement Z.K. reports financial support from DeuterOncology NV outside the submitted work. B.C.C. reports stock ownership with TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence Corp and J INTS BIO; reports participating in an advisory role for KANAPH Therapeutic Inc, Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health and Oscotec; has received consulting fees from Novartis, Abion, BeiGene, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol-Myers Squibb, ONO, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, Medpacto, and Blueprint medicines; has received grants or funds from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, ONO, Dizal Pharma, MSD, Abbvie, Medpacto, GI Innovation, Eli Lilly, Blueprint medicines, and Interpark Bio Convergence Corp; has received royalties from Campions Oncology, Crown Bioscience and Imagen; and is the founder of DAAN Biotherapeutics. A.B.C. has received honorarium for advisory positions, board memberships, lectures or non-financial support from the following sources: Astra-Zeneca, Roche, MSD, Pfizer, Novartis, Takeda, Janssen, Abbvie, Amgen. L.G. is inventor of a patent on DNA barcoding issued to Inserm and University of Rouen.