TY - JOUR
T1 - Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
AU - Fernandes Neto, João M
AU - Nadal, Ernest
AU - Bosdriesz, Evert
AU - Ooft, Salo N
AU - Farre, Lourdes
AU - McLean, Chelsea
AU - Klarenbeek, Sjoerd
AU - Jurgens, Anouk
AU - Hagen, Hannes
AU - Wang, Liqin
AU - Felip, Enriqueta
AU - Martinez-Marti, Alex
AU - Vidal, August
AU - Voest, Emile
AU - Wessels, Lodewyk F A
AU - van Tellingen, Olaf
AU - Villanueva, Alberto
AU - Bernards, René
PY - 2020/6/22
Y1 - 2020/6/22
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-16952-9
DO - 10.1038/s41467-020-16952-9
M3 - Article
C2 - 32572029
SN - 2041-1723
VL - 11
SP - 3157
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3157
ER -