Nuclear interaction of Arp2/3 complex and BRAF V600E promotes aggressive behavior and vemurafenib resistance of thyroid cancer

• Published in: American journal of cancer research 2022, Vol.12 (7), p.3014
• Main Authors: Zerfaoui, Mourad, Tsumagari, Koji, Toraih, Eman, Errami, Youssef, Ruiz, Emmanuelle, Elaasar, Mohammed Sohail M, Krzysztof, Moroz, Sholl, Andrew B, Magdeldin, Sameh, Soudy, Mohamed, Abd Elmageed, Zakaria Y, Boulares, A Hamid, Kandil, Emad
• Format: Article
• Language: English
• ISSN: 2156-6976; 2156-6976

The presence of mutant BRAF correlates with the risk of recurrence in papillary thyroid cancer (PTC) patients. However, not all PTC patients with BRAF are associated with poor prognosis. Thus, understanding the mechanisms by which certain PTC patients with nuclear BRAF become aggressive and develop resistance to a selective BRAF inhibitor, PLX-4032, is urgently needed. The effect of nuclear localization of BRAF using studies, xenograft mouse-model and human tissues was evaluated. PTC cells harboring a nuclear localization signal (NLS) of BRAF were established and examined in nude mice implanted with TPC1-NLS-BRAF cells followed by PLX-4032 treatment. Immunohistochemical (IHC) analysis was performed on 100 PTC specimens previously confirmed that they have BRAF mutations. Our results demonstrate that 21 of 100 (21%) PTC tissues stained with specific BRAF antibody had nuclear staining with more aggressive features compared to their cytosolic counterparts. studies show that BRAF is transported between the nucleus and the cytosol through CRM1 and importin (α/β) system. Sequestration of BRAF in the cytosol sensitized resistant cells to PLX-4032, whereas nuclear BRAF was associated with aggressive phenotypes and developed drug resistance. Proteomic analysis revealed Arp2/3 complex members, actin-related protein 2 (ACTR2 aliases ARP2) and actin-related protein 3 (ACTR3 aliases ARP3), as the most enriched nuclear BRAF partners. ACTR3 was highly correlated to lymph node stage and extrathyroidal extension and was validated with different functional assays. Our findings provide new insights into the clinical utility of the nuclear BRAF as a prognostic marker for PTC aggressiveness and determine the efficacy of selective BRAF inhibitor treatment which opens new avenues for future treatment options.