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

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.

• Authors: João M Fernandes Neto, Ernest Nadal, Evert Bosdriesz, Salo N Ooft, Lourdes Farre, Chelsea McLean, Sjoerd Klarenbeek, Anouk Jurgens, Hannes Hagen, Liqin Wang, Enriqueta Felip, Alex Martinez-Marti, August Vidal, Emile Voest, Lodewyk F A Wessels, Olaf van Tellingen, Alberto Villanueva, René Bernards
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 3157 (Jun 22 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32572029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• EGFR protein, mouse
• ErbB Receptors

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, toxicity)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Humans
• Lung Neoplasms (drug therapy)
• MAP Kinase Signaling System (drug effects)
• Mice
• Models, Animal
• Mutation
• Protein Kinase Inhibitors (administration & dosage, pharmacology, toxicity)
• Tumor Cells, Cultured