NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2^(V617F)-positive myeloproliferative neoplasm cells

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms(MPN);in this pathway,IRS2 is involved in the malignant transformation induced by JAK2^(V617F),and upregulation of IGF1R signaling induces the MPN phenotype.NT157,a synthetic compound designed as an IGF1R-IRS1/2 inhibitor,has been shown to induce antineoplastic effects in solid tumors.Herein,we aimed to characterize the molecular and cellular effects of NT157 in JAK2^(V617F)positive MPN cell lines(HEL and SET2)and primary patient hematopoietic cells.In JAK2^(V617F)cell lines,NT157 decreased cell viability,clonogenicity,and cell proliferation,resulting in increases in apoptosis and cell cycle arrest in the G2/M phase(p<0.05).NT157 treatment inhibited IRS1/2,JAK2/STAT,and NFκB signaling,and it activated the AP-1 complex,downregulated four oncogenes(CCND1,MYB,WT1,and NFKB1),and upregulated three apoptotic-related genes(CDKN1A,FOS,and JUN)(p<0.05).NT157 induced genotoxic stress in a JAK2/STAT-independent manner.NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients(p<0.05).These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.

Is the EGFR pathway relevant for the pathogenesis but not for treatment of acute myeloid leukemia?

Despite intense research and the development of several new chemotherapeutics,the prognosis for specific subsets of acute myeloid leukemia(AML)has not improved significantly.Thus,the investigation of signaling pathways associated with the pathogenesis and progression of AML has become a source for the discovery of more effective treatments.The epidermal growth factor receptor(EGFR)belongs to the HER family of tyrosine kinase(TK)receptors and is involved in the progression of a variety of solid tumors.Although the expression of members of the HER family appears to be limited to epithelial tissues and derived neoplasms,there is evidence demonstrating their role in hematopoiesis and hematological neoplasms.In AML,preclinical studies and two anecdotal cases of response to EGFR TK inhibitors(TKI)supported the EGFR signaling pathway as a potential therapeutic target.Indeed,the presence of EGFR ligands in the bone marrow microenvironment has been shown to play pathological and regenerative/protective roles in AML.However,data reporting the expression of EGFR in AML remain controversial and the EGFR pathway inhibition in AML patients has demonstrated limited clinical significance.Further studies are required to determine the relevance of the EGFR pathway in AML biology and which patients may benefit from using EGFR TKI or other drugs that target TK receptors.