Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibidor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibidor therapy. ; This work was supported by a grant from the Dutch Cancer Society through the Oncode Institute. Al.V. was supported by the Fondo de Investigaciones Sanitarias, FIS (PI16-01898, and by the Spanish Association Against Cancer, AECC (CGB14142035THOM) and Ideas Semilla project (IDEAS098VILL-IDEAS16) and Generalitat de Catalunya (2014SGR364). L.F. received a European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie, grant agreement number 799850. E.N. was funded by Instituto Carlos III through the project PI18/00920. We thank CERCA Program/Generalitat de Catalunya for their institutional support and grant 2017SGR448.
