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22Jun 2020

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Less drug, more effect

Combining low doses of several cancer drugs at the same time might overcome the important problem of resistance, researchers from the Netherlands Cancer Institute conclude. In the lab this multiple low dose approach shows promising results, they describe in the scientific journal Nature Communications today.

Resistance is a major problem in the treatment of cancer patients. Drugs targeting specific signaling proteins within cancer cells can work very well initially. In the end though, the tumor becomes resistant and starts growing again. That's why scientists and clinicians focus their attention on outsmarting cancer by combining different drugs. A cocktail of drugs that block several parts of the same signal route in cancer cells, for example, has proven effective, but patients can experience severe side effects.

Nothing plus nothing

Researchers of the Netherlands Cancer Institute think they might have found a way around this problem: multiple low dose therapy. Combining four carefully selected drugs at very low doses appears to block cancer signals very well in the lab, without significant side effects. "Initially, we didn't think it was going to work so well", says researcher and first author of the publication João Neto. "Each drug individually has no effect at all when used in such a low dose. So: nothing plus nothing would be… nothing, right? But we saw a huge synergy when we combined the four drugs at low concentration!"

Four drugs

The researchers treated both lung cancer cells and mice with lung cancer with four medicines carrying the not so appealing names EGFR, RAF, MEK and ERK inhibitors. Why these? They're all blocking proteins that are part of the same communication route within the cell. And the cells of certain lung cancers are addicted to it. They have a mutation in the EGFR gene, making this signal route hyperactive and cell division go through the roof. Patients initially respond well to drugs against EGFR, but once resistant cells find their way around the blockage there aren't a lot of treatment options left.

Blocking crossroads

Hence the idea of outsmarting the cancer cells by blocking several crossroads instead of one.

João and his colleagues found out they could block the signaling route completely with as little as one fifth of the individual effective drug dose. The cells stopped dividing and died. No resistance. "In mice the tumors also shrank", he says. "They didn't disappear completely, like the cells in the lab, because the mice degraded some of the drugs very fast. So, one of the challenges when testing this in human patients will be to sustain the right level of drug in their bodies."

Multiple low dose treatment

That's right, testing in patients will be the next step. Researchers and clinicians at the Netherlands Cancer Institute still have quite some work to do though, such as translating the current findings in cells and mice to the exact right doses in humans, securing the drugs to be used in the trial, and convince funders to support this important step into the clinic.

"The potential of multiple low dose treatment goes beyond lung cancer", says João. "We tested cells of several other cancer types and saw the same promising results. In theory it can be applied to a broad range of tumors, as long as they are addicted to a communication pathway within their cells."

This research was financially supported by the Dutch Cancer Foundation and Oncode Institute.

Read more:

  • Tweetorial, in which Joao neatly summarizes his research
  • The publication in Nature Communications
  • Recent findings of the same Rene Bernard lab on another innovative approach to combination therapy: the one-two-punch.
Afbeelding Multiple Low Dose Therapy












Low doses of four medicines administered simultaneously effectively inhibit this essential signal route in cancer cells (EGFR-, RAF-, MEK- and ERK-inhibitors).

About the research

Treatment: Multiple low dose therapy

Tumor type: Lung cancer (EGFR mutant)

Research phase: Preclinical and translational

Tested in: Cancer cells and mice

Research from: The Netherlands and Spain



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