SUMMARY:
UCLA researchers in the Department of Medicine have developed a novel therapeutic method to prevent acquired resistance to MAPK drug inhibition in melanoma.
BACKGROUND:Melanoma is the fifth most common cancer in the United States and the most fatal of all skin cancer types. Typical treatments of melanoma tumors include pharmacological drugs that inhibit BRAF and MEF, which are critical regulators of the MAPK pathway. While these inhibitors are highly effective for many patients, mortality from melanoma remains high because of the high rate of therapeutic resistance, wherein melanoma tumors become resistant to MAPK inhibitors after several months of therapy. Drug-resistant tumors are more aggressive and more likely to become fatal. Research has shown that tumor resistance to melanoma therapies reactivates the MAPK pathway through high magnitude gene amplifications. Thus, treatments that target altered phenotypes to overcome acquired resistance to MAPK-targeted therapy could profoundly improve survival rates of melanoma.
INNOVATION:Researchers at UCLA let by Dr. Roger Lo have discovered a novel technique for suppressing acquired MAPKi resistance in human melanoma cells through inhibition of critical proteins in the pathways of resistance evolution. The UCLA researchers sought to understand the source of genomic instability in melanoma drug-resistant tumors and found that DNA signatures of chromothripsis, a mutational phenomenon consisting of extensive genomic rearrangements, are strongly associated with MAPKi resistance. They used breakpoint-sequence analysis to identify key pathways of chromothripsis. In human melanoma cell lines and patient-derived xenografts in murine models, the Lo group demonstrated that co-inhibition of two critical proteins in these pathways led to additive or synergistic suppression of acquired MAPK inhibitor resistance. Inhibiting the mechanisms of genomic instability that breed drug resistance could be a novel and effective method to improve melanoma treatment.
POTENTIAL APPLICATIONS:
• Improve MAPK inhibitor-based treatments of melanoma tumors
• Identify therapy resistant or aggressive melanoma by detection of chromothriptic DNAs in the tumor cells

ADVANTAGES:
• Effectively prevents acquired drug -resistance via genomic instability
• Wide-reaching detection of chromothripsis includes tumor, circulating tumor cells, and circulating tumor-free DNAs
• Discovery of various pathways involved in resistance evolution and chromothripsis allow for personalized therapy
DEVELOPMENT-TO-DATE:
UCLA researchers have demonstrated that co-inhibition of two critical proteins involved in the pathways of chromothripsis successfully suppress acquired MAPKi resistance Proof of concept established in human melanoma cell lines and patient-derived xenografts in murine models.