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Treatment-resistant melanoma may be vulnerable to a drug holiday

Staff Writer |
A UCLA study has uncovered the mechanisms by which treatment-resistant melanoma become vulnerable to a drug holiday of a class of drugs called MAP kinase (MAPK)-targeted inhibitors.

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By identifying these mechanisms, the scientists discovered that therapeutic benefits for patients could derive from a one-two punch of cessation of MAPK inhibitors followed by a class of drugs called DNA repair inhibitors.

The findings, which were demonstrated in several major subtypes of melanoma tumors (including BRAF and NRAS melanoma), could lead to drug development strategies that suppress the development of drug resistance.

Approximately 50 percent of advanced melanoma tumors are driven to grow by the presence of BRAF mutations and another 20 percent by the presence of NRAS mutations. These mutations drive the MAPK cancer growth and survival pathway.

MAPK-targeted inhibitors, such as BRAF and MEK inhibitors, selectively block key cancer-driving signals. However, not everyone's melanoma will benefit equally from MAPK-targeted therapies, and initial benefits might wane over time as tumors develop resistance to treatment.

The new study's findings build upon prior research by Dr. Roger Lo, a professor of medicine (dermatology) and molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

His team discovered that treatment-resistant melanoma tumors, in what is akin to drug addiction, develop a dependency on MAPK-targeted therapy to retain their fitness. Thus, when treatment is discontinued, withdrawal occurs and the tumor weakens.

Lo's team set out to find ways to further weaken the tumors, since the drug addiction response (which can range from a mere slow down of the cancer's growth rate to cancer cell death), can be used to improve clinical outcomes.

Recent clinical studies and case reports indicate that, for patients who have relapsed on MAPK-targeted inhibitors, re-introduction of MAPK therapy following an intentional drug holiday may lead to a secondary response.

This suggests that in patients, drug-resistant tumor cells might be replaced by drug-sensitive tumor cells during the drug holiday.

Along with the study's co-first authors, Drs. Aayoung Hong and Gatien Moriceau, Lo hypothesized that if they could identify the key tumor cell processes triggered by withdrawal of MAPK inhibitors, then scientists can exploit these process with existing or investigational drugs to trigger the maximal levels of tumor cell death immediately following cessation of the initial therapy.


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