AI Article Synopsis
- Resistance to targeted cancer drugs often arises from high drug doses that create selective pressure, but a new approach called Multiple Low Dose (MLD) therapy might mitigate this issue.
- MLD therapy involves using lower doses (as little as 20%) of multiple drugs that target the same cancer pathway, effectively blocking key signaling and preventing cell proliferation without developing resistance.
- Animal studies show that MLD therapy leads to lasting positive responses in EGFR mutant non-small cell lung cancer (NSCLC) without harmful side effects, suggesting its potential for clinical use, especially in patients with resistance to existing treatments.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308397 | PMC |
| http://dx.doi.org/10.1038/s41467-020-16952-9 | DOI Listing |
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