Translational research of combined anticancer therapies targeting the MAPK pathway

Abstract

Due to abnormalities in the DNA (mutations) of cancer cells, specific proteins can become hyperactive leading to cancer grow. By inhibiting these proteins with targeted drugs, this growth might be prevented. Many of these drugs have been developed in recent years, but the results are sometimes disappointing. The cancer cell can switch to an alternative survival signal, which makes the targeted therapy no longer effective. This is called resistance, which may be present at treatment start or develop during treatment. By also inhibiting the proteins that cause resistance, the effectiveness of anticancer treatment might be improved. The drug combinations in this thesis focus on overcoming resistance and specifically target abnormal BRAF or KRAS proteins. Patients with such proteins often have a poor prognosis and respond poorly to regular anticancer therapies. Combining multiple drugs simultaneously or intermittently might enhance the anticancer effect. Promising results have been achieved in studies in patients with colon cancer and an abnormal BRAF protein. In these patients, concomitant treatment with the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab with or without the MEK inhibitor binimetinib has been shown to be safe and effective. Recently, the combination is approved for this patient group in the USA and Europe. Furthermore, this thesis describes the intermittent treatment of patients with melanoma and an abnormal BRAF protein resistant to BRAF inhibitors. Finally, 3 phase I studies are described that investigate the safety of different combinations of HER and MEK inhibitors in patients with tumors with an abnormal KRAS protein.