Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

João M Fernandes Neto,August Vidal,Alex Martinez-Marti,Evert Bosdriesz,Emile Voest,Liqin Wang,Ernest Nadal,Hannes Hagen,Lourdes Farre,Anouk Jurgens,Olaf Van Tellingen,Chelsea Mclean,Alberto Villanueva,Salo N Ooft,Enriqueta Felip,Sjoerd Klarenbeek,René Bernards,Lodewyk F A Wessels

doi:10.1038/s41467-020-16952-9

Abstract

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) inhibitor 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 inhibitor therapy.

Highlights

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose
We explore the use of a Multiple Low Dose (MLD) strategy in EGFR mutant non-small cell lung cancer (NSCLC)
We compared the efficacy of MLD therapy to standard-ofcare maximum tolerated dose (MTD) therapies in this indication

Summary

Introduction

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. In BRAF mutant melanoma and non-small cell lung cancer (NSCLC), inhibition of two components of the same oncogenic pathway (BRAF + MEK, referred to as “vertical targeting”) has been shown to provide more lasting clinical benefit compared to inhibition of only BRAF4,5. Both clinical[6,7] and pre-clinical[8] studies have shown that inhibition of three components of the same oncogenic pathway further increases therapeutic benefit. We explore the use of a Multiple Low Dose (MLD) strategy in EGFR mutant NSCLC In this approach, multiple drugs that act in the same oncogenic signalling pathway are combined at low concentration. By using low drug concentrations, the pressure exerted on each node of the pathway should greatly diminish, reducing the selective pressure on each node and diminishing the chances of acquiring resistance

Methods

Results

Conclusion