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. Dutch researchers at the Netherlands Cancer Institute (NKI) have developed a strategy combining low doses of four known anticancer drugs, with promising results in cells as well as mice. An article about this research recently appeared in Nature Communications.
Specifically, the multiple low dose (MLD) therapy was tested on EGFR mutant non small cell lung cancer (NSCLC). The researchers found that as little as 20% of the individual effective drug doses was sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Furthermore, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, the researchers noted durable responses to MLD therapy without associated toxicity. The conclusion is that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.
According to research leader João Neto, administering the four drugs separately in a low dose have no effect, and he admits that he and his team were surprised to see the efficacy of the combination of four different low dose drugs. “We saw enormous synergy when we combined the four drugs”, he says. By applying four different drugs, cancer cells are attacked in four different places instead of just one. Neto and his team discovered that just 20% of the normal dosage was already sufficient to block protein pathways, leading to cell death. The researchers did note that the effect of the MLD combo worked better in laboratory-created cancer cells than they did in mice, but it is well known that mice are able to metabolize certain drugs very rapidly. “One of the main challenges when it comes to testing the MLD combination in human patients will be maintaining the correct level of medicine”, Neto explains. Before the therapy can be tested in humans, the correct dosage needs to be established.
Meanwhile, the researchers from Amsterdam are already examining future possibilities for the MLD treatment. Tests have been performed at the NKI on different types of cancer cell, and the results have been similar. Neto: “Theoretically the MLD combination strategy could be applied to a wide range of tumours.”
Fernandes Neto, J.M., Nadal, E., Bosdriesz, E. et al. Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours. Nat Commun 11, 3157 (2020). https://doi.org/10.1038/s41467-020-16952-9