![]() ![]() Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung. Shin DH, Lee D, Hong DW, Hong SH, Hwang J-A, Lee BI, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. 2011 71:1071–80.Īrdito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, et al. Oncogenic Kras promotes chemotherapy-induced growth factor shedding via ADAM17. Van Schaeybroeck S, Kyula JN, Fenton A, Fenning CS, Sasazuki T, Shirasawa S, et al. ![]() ADAM17: An emerging therapeutic target for lung cancer. Biochimica et Biophysica Acta (BBA)-Mol Cell Res. The shedding protease ADAM17: Physiology and pathophysiology. ADAM 17 selectively activates the IL‐6 trans‐signaling/ERK MAPK axis in KRAS‐addicted lung cancer. Saad MI, Alhayyani S, McLeod L, Yu L, Alanazi M, Deswaerte V, et al. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2009 4:1064.Ĭox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Johnson L, Greenbaum D, Cichowski K, Mercer K, Murphy E, Schmitt E, et al. Preoperative chemotherapy for non-small-cell lung cancer: A systematic review and meta-analysis of individual participant data. Incidence and mortality of lung cancer: Global trends and association with socioeconomic status. Wong MC, Lao XQ, Ho K-F, Goggins WB, Shelly L. Moreover, the coexistence of KRAS mutant and S-N fusion in lung tumours renders them vulnerable to MEK1/2 and/or ADAM17 inhibitors, at least in part, due to their dependency on the strong positive loop between KRAS mutation and S-N fusion. Taken together, this is the first study to report that KRAS mutation increased NRG1 cleavage from the S-N fusion protein through ADAM17, thereby enhancing the Ras/Raf/MEK/ERK and ERBB/PI3K/Akt/mTOR pathways. Targeted inhibition of MEK1/2, and ADAM17 significantly induced apoptosis singly and when combined with each mutation singly or with chemotherapy in both the concurrent KRAS mutant and S-N fusion xenograft and lung orthotopic models. ![]() The concurrence of S-N fusion and KRAS mutation synergistically increased cell proliferation, colony formation, tumour growth, and the cells’ resistance to EGFR kinase inhibitors more than KRAS mutation alone. The cleavage of NRG1 also increased the phosphorylation of ERBB2-ERBB3 heterocomplex receptors and their downstream signalling pathways, including PI3K/Akt/mTOR, even under activated KRAS mutation signalling. KRAS mutation-mediated increase in MEK1/2 and ERK1/2 activity enhanced disintegrin and metalloproteinase (ADAM)17 activity, which increased the shedding of NRG1 from the S-N fusion protein. In this study, we examined the role of mutant KRAS in regulating the S-N fusion protein in KRAS mutant (H358) and wild-type (Calu-3) cells. Interestingly, KRAS mutation coexisted (62.5%) in 10 out of 16 NRG1 fusions. We previously found the SLC3A2-NRG1 ( S-N) fusion gene in a lung adenocarcinoma specimen without known driver mutations and validated this in 59 invasive mucinous adenocarcinoma (IMA) samples. ![]()
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