RT Journal Article
SR Electronic
T1 Multiple Low Dose (MLD) therapy: an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 821975
DO 10.1101/821975
A1 João M. Fernandes Neto
A1 Ernest Nadal
A1 Salo N Ooft
A1 Evert Bosdriesz
A1 Lourdes Farre
A1 Chelsea McLean
A1 Sjoerd Klarenbeek
A1 Anouk Jurgens
A1 Hannes Hagen
A1 Liqin Wang
A1 Enriqueta Felip
A1 Alex Martinez-Marti
A1 Emile Voest
A1 Lodewyk F.A. Wessels
A1 Olaf van Tellingen
A1 Alberto Villanueva
A1 René Bernards
YR 2019
UL http://biorxiv.org/content/early/2019/10/29/821975.abstract
AB Targeted cancer drugs often elicit powerful initial responses, but generally fail to deliver long-term benefit due to the emergence of resistant cells1,2. This is thought to be the consequence of strong selective pressure exerted on the cancer drug target by a Maximum Tolerated Dose (MTD) of a drug3–5. We hypothesized that partial inhibition of multiple components in the same oncogenic signalling pathway might add up to complete pathway inhibition, while at the same time decreasing the selective pressure on each individual component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) model of drug administration in Epidermal Growth Factor Receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We show that as little as 20% of the individual drug doses required for full inhibition of cell viability is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF+MEK+ERK inhibitors) or 4D (EGFR+RAF+MEK+ERK inhibitors) combinations. Importantly, EGFR mutant NSCLC cells treated with EGFR inhibitors at a high dose rapidly developed resistance in vitro, but the cells treated with 3D or 4D MLD therapy did not. Moreover, NSCLC cells that had gained resistance to high dose anti-EGFR therapies were still sensitive to MLD therapy. Using several animal models, including patient derived xenografts of NSCLC tumours that are resistant to EGFR inhibitors erlotinib and osimertinib6,7, we found durable responses to MLD therapy without associated toxicity. These data support the notion that partial inhibition of multiple components of cancer-activated signalling pathways is difficult to circumvent and suggest that MLD therapy could deliver clinical benefit. We propose that MLD strategy could be an effective treatment option for EGFR mutant NSCLC patients, especially those having acquired resistance to even third generation EGFR inhibitor therapy.