Nature Sub-journal: Challenging classic, multi-low-dose drug combinations are effective in treating non-small cell lung cancer without resistance.

Inhibition of signaling pathways activated by carcinogenic mutations can trigger therapeutic responses. However, in advanced cancer, drug resistance is virtually inevitable because secondary mutations can restore signal transduction through drug inhibition.it is believed that drug resistance to targeted cancer drugs is due to the selective pressure generated by high-dose drugs.previous studies have shown that inhibition of two components of the same carcinogenic pathway (BRAF + MEK) in BRAF mutant melanoma and non-small cell lung cancer (NSCLC) shows more sustained clinical benefits than inhibition of BRAF alone.recent preclinical studies have found that inhibition of three components of the same carcinogenic pathway can further improve the therapeutic effect.in these cases, the drug is usually administered at the maximum tolerable dose (MTD).however, an increase in the number of drugs used in combination is usually accompanied by an increase in toxicity, but so far, few studies have evaluated the efficacy of a combination of drugs below the maximum tolerable dose (MTD).can the strategy of multiple low-dose (MLD) drug combination reduce drug resistance caused by high-dose drugs on the basis of effective treatment? Recently, Ren é Bernards et al. Published a research paper entitled "multiple low dose therapy as an effective strategy to treat EGFR inhibitor resistant NSCLC tumours" in nature communications.in this study, the EGFR mutant non-small cell lung cancer model was used to test the multiple low-dose (MLD) treatment. The experimental results showed that when the triple low-dose (RAF + MEK + ERK) or the quadruple low-dose (EGFR + RAF + MEK + ERK), the single effective dose as low as 20% was sufficient to completely block MAPK signal transduction and cancer cell proliferation.more importantly, multiple low-dose (MLD) treatment of EGFR mutated non-small cell lung cancer cells did not produce drug resistance. In several animal models, multiple low-dose (MLD) treatment was found to be persistent and non-toxic.it is believed that drug resistance to targeted cancer drugs is due to the selective pressure generated by high-dose drugs.partial inhibition of multiple components in the same carcinogenic signaling pathway is enough to completely inhibit the whole pathway, while reducing the selective pressure on each component to reduce acquired resistance mutations.to test the hypothesis, the team tested multiple low-dose (MLD) treatment models in EGFR mutant non-small cell lung cancer (NSCLC).the results showed that the single effective dose of 20% was enough to completely block MAPK signal transduction and cancer cell proliferation when using triple low dose (RAF + MEK + ERK) or quadruple low dose (EGFR + RAF + MEK + ERK).more importantly, multiple low-dose (MLD) treatment of EGFR mutated non-small cell lung cancer cells did not produce drug resistance. In several animal models, multiple low-dose (MLD) treatment was found to be persistent and non-toxic.experimental data show that multiple low-dose (MLD) treatment can bring clinical benefits even in patients with resistance to third-generation EGFR inhibitors.in this study, inhibition of the carcinogenic pathway at multiple nodes reduced the selective pressure of mutation at each node, thus increasing the effective response time of cancer treatment.although this study is aimed at EGFR mutant non-small cell lung cancer, multiple low-dose (MLD) treatment strategies may also be effective for other types of tumors. in general, multiple low-dose (MLD) therapy for EGFR mutated non-small cell lung cancer (NSCLC) can effectively inhibit the development of drug resistance without associated toxicity. this study challenges the general practice of treating patients with maximum tolerable dose (MTD). It may be more beneficial to use a combination of low-dose drugs targeting the carcinogenic activation pathway. paper links: