Advancement in research and therapy of NF1 mutant malignant tumors
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Cancer Cell International Open Access
REVIEW
Advancement in research and therapy of NF1 mutant malignant tumors Junyan Tao, Dantong Sun, Lina Dong, Hua Zhu* and Helei Hou*
Abstract The NF1 gene encodes neurofibromin, which is one of the primary negative regulatory factors of the Ras protein. Neurofibromin stimulates the GTPase activity of Ras to convert it from an active GTP-bound form to its inactive GDPbound form through its GTPase activating protein-related domain (GRD). Therefore, neurofibromin serves as a shutdown signal for all vertebrate RAS GTPases. NF1 mutations cause a resultant decrease in neurofibromin expression, which has been detected in many human malignancies, including NSCLC, breast cancer and so on. NF1 mutations are associated with the underlying mechanisms of treatment resistance discovered in multiple malignancies. This paper reviews the possible mechanisms of NF1 mutation-induced therapeutic resistance to chemotherapy, endocrine therapy and targeted therapy in malignancies. Then, we further discuss advancements in targeted therapy for NF1-mutated malignant tumors. In addition, therapies targeting the downstream molecules of NF1 might be potential novel strategies for the treatment of advanced malignancies. Keywords: NF1, Ras, Therapeutic resistance, Molecular mechanism, Malignancies Background With the aging population and changes in lifestyle, the morbidity and mortality rates of malignancies in the world are rising drastically. In 2018, 18.1 million new cases and 9.6 million cancer deaths were registered worldwide [1]. Treatments for advanced malignant tumors, including traditional treatment (surgery combined with radiotherapy and chemotherapy), targeted therapy and immunotherapy, significantly prolong the survival of patients with malignancies. To date, targeted therapies have achieved significant advances. The studies on the driven mutations of malignancies, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and human epidermal growth factor receptor-2 (HER2), have brought clinical benefits and more therapeutic options for patients with malignancies [2–4]. Patients harboring
*Correspondence: [email protected]; [email protected] Precision Medicine Center of Oncology, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, Shandong 266000, China
sensitive mutations benefit from targeted therapy. However, drug resistance remains a serious problem during treatment. Drug resistance limits the use of targeted therapy in malignant tumors and is one of the foremost challenges in malignant tumors today [5]. Neurofibromin 1 (NF1) mutations cause an autosomal dominant genetic susceptibility syndrome known as neurofibromatosis type 1 [6]. Furthermore, genomic data from the cBioPortal for Cancer Genomics datasets indicate that somatic NF1 mutations can be detected in a variety of malignancies, including non-small-cell lung cancer (NSCLC), ovarian cancer, breast cancer, liver cancer, and esophagogastric cancer. The a
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