As targeted drugs play an increasingly important role in the field of tumor treatment, how to solve the problem of drug resistance has also been repeatedly mentioned. How to maximize the use time of targeted drugs and allow patients to obtain high-quality survival time is the vision of every medical worker.
At present, the anti-tumor drugs taken by patients directly or indirectly affect the proliferation of tumor cells by combining with the relevant molecules of tumor cells and achieve the purpose of anti-tumor. Through the unremitting efforts of researchers, it has been found that some drugs that we did not expect will also play a role in the pathway of molecular interaction, and even prolong the time of targeted drug resistance. In the following article, cancer degree takes you to explore together.
Autophagy and targeted drug resistance
First, let's understand a concept: "autophagy". Cells destroy some damaged proteins or organelles, which are wrapped in "autophagic vesicles" and then sent into lysosomes for degradation and recycling, similar to a garbage disposal and recycling system, in normal cells, autophagy is an important physiological process to maintain operation.
However, autophagy is sometimes used by cancer cells, such as the drugs we use, which may be degraded by cancer cells. There is already evidence that autophagy plays an important role in the targeted therapy resistance of the MAPK signaling pathway.
Now that the problem of autophagy has been found, it is necessary to find a corresponding drug to restrain it. Researchers have confirmed in clinical trials that hydroxychloroquine, a drug that prevents and treats malaria, can effectively block autophagy. Hydroxychloroquine is also approved by the U.S. FDA for the treatment of rheumatoid arthritis and lupus.
Based on these principles, the researchers envision a combination of targeted drugs and hydroxychloroquine to see if a better therapeutic effect can be achieved.
Darafenib, trimetinib combined with hydroxychloroquine for the treatment of melanoma
Melanoma is a very common malignancy, for this tumor is more common genetic mutation - BRAF gene V600E, there are corresponding targeted drugs verofinib and darafenib. Downstream of the BRAF gene is the MEK gene, so a very good therapeutic effect has now been achieved in the treatment of melanoma by combining dalafenib, which blocks the BRAF gene, and trimetinib, which blocks meK.
Due to the rise of immunotherapy represented by PD-1 inhibitors, many melanoma patients often use PD-1 inhibitors when initially diagnosing the disease, and then use targeted drugs after immunotherapy resistance. Around these questions, the researchers initiated a Phase I/II clinical trial.
A total of 34 patients were enrolled, all of whom were patients with advanced melanoma, of which 47% had a high lactate dehydrogenase (LDH) and 50% had previously used immunotherapy and were resistant. The drugs used in the enrolled patients were hydroxychloroquine (HCQ) 600 mg, darafenib 150 mg twice a day, and trametinib 2 mg (once a day).
The results showed that this combination of treatment did not produce dose-limiting toxicity, the proportion of patients with no progression in one year was 48.2%, the median progression-free survival was 11.2 months, and the median overall survival was 26.5 months, and the combination of drugs produced a response rate of up to 85%, of which the complete response rate reached 41%.
Figure 1. Response rate of hydroxychloroquine, trammetinib, and darafenib in the treatment of melanoma
In patient populations with high lactate dehydrogenase (LDH), treatment response rates were achieved 88%, median progression-free survival was 7.3 months, and median overall survival was 22 months.
The researchers' final assessment was that the combination of the three drugs produced a very high rate of response to treatment, but the proportion of diseases that did not progress in one year of treatment did not meet expectations. Among the patients enrolled in the study, lactate dehydrogenase (LDH) was high and the proportion of patients who had been treated with immunotherapy was high. These factors may have an impact on treatment outcomes, and new clinical studies are currently underway.
Fig. 2. Survival of hydroxychloroquine combined with trimetinib and darafenib in the treatment of melanoma
Revelation: Do you want to use hydroxychloroquine now?
Cancer degree is always the first time to share the latest information and research results in the field of tumor treatment, we hope that patients and friends can get some references from it, or benefit from our information sharing.
Although hydroxychloroquine is common above, and darafenib and trimetinib are also on the market, more clinical trials are needed for the combination of these three drugs to obtain a clear reference basis.
Therefore, in the actual treatment process, patient friends should still follow the opinion of the attending doctor and treat according to the standardized measures. We believe that these clinical trials, which are still under exploration and research, will one day become standardized treatments and bring real benefits to patients.
参考文献：Janice M Mehnert et al., BAMM (BRAF Autophagy and MEK inhibition in Melanoma): A phase I/II trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600-mutant melanoma，Clin Cancer Res. 2022 Jan 12.