ARAFmutations confer resistance to the RAF inhibitor belvarafenib in melanoma

Autor: Yen, Ivana, Shanahan, Frances, Lee, Jeeyun, Hong, Yong Sang, Shin, Sang Joon, Moore, Amanda R., Sudhamsu, Jawahar, Chang, Matthew T., Bae, Inhwan, Dela Cruz, Darlene, Hunsaker, Thomas, Klijn, Christiaan, Liau, Nicholas P. D., Lin, Eva, Martin, Scott E., Modrusan, Zora, Piskol, Robert, Segal, Ehud, Venkatanarayan, Avinashnarayan, Ye, Xin, Yin, Jianping, Zhang, Liangxuan, Kim, Jin-Soo, Lim, Hyeong-Seok, Kim, Kyu-Pyo, Kim, Yu Jung, Han, Hye Sook, Lee, Soo Jung, Kim, Seung Tae, Jung, Minkyu, Hong, Yoon-hee, Noh, Young Su, Choi, Munjeong, Han, Oakpil, Nowicka, Malgorzata, Srinivasan, Shrividhya, Yan, Yibing, Kim, Tae Won, Malek, Shiva
Zdroj: Nature; June 2021, Vol. 594 Issue: 7863 p418-423, 6p
Abstrakt: Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600mutant cells1–3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E-and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAFwithin the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAFmutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAFmutations as a driver of resistance to RAF dimer inhibitors.
Databáze: Supplemental Index
Externí odkaz: