Inducible SHP-2 activation confers resistance to imatinib in drug-tolerant chronic myeloid leukemia cells.

BCR-ABL kinase mutations, accounting for clinical resistance to tyrosine kinase inhibitor (TKI) such as imatinib, frequently occur in acquired resistance or in advanced phases of chronic myeloid leukemia (CML). Emerging evidence implicates a critical role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. Here, we utilized non-mutational imatinib-resistant K562/G cells to reveal SHP-2 as a resistance modulator of imatinib treatment response during the early phase. SHP-2 phosphorylation was significantly higher in K562/G cells than in sensitive K562 cells. In K562 cells, both short-term and long-term exposure to imatinib induced SHP-2 phosphorylation. Consistently, gain- and loss-of-function mutants in SHP-2 proved its regulation of imatinib resistance. SHP-2 inhibitor and imatinib exhibited a strong antitumor synergy in in vitro and in vivo K562/G models. Mechanistically, dual SHP-2 and BCR-ABL inhibition blocked RAF/MEK/ERK and PI3K/AKT/mTOR pathways, respectively, leading to dramatic apoptotic death of K562/G cells. In conclusion, our results highlight that SHP-2 could be exploited as a biomarker and therapeutic target during the early phase of imatinib resistance development in CML.

Li X ，Pang J ，Xue W ，Wang Y ，Tian T ，Elgehama A ，Wu X ，Wu X ，Sun Y ，Qiu H ，Shen Y ，Xu Q ... -  《-》

Inhibition of protein kinase CK2 by CX-5011 counteracts imatinib-resistance preventing rpS6 phosphorylation in chronic myeloid leukaemia cells: new combined therapeutic strategies.

Salizzato V ，Borgo C ，Cesaro L ，Pinna LA ，Donella-Deana A ... -  《Oncotarget》

Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors.

Wöhrle FU ，Halbach S ，Aumann K ，Schwemmers S ，Braun S ，Auberger P ，Schramek D ，Penninger JM ，Laßmann S ，Werner M ，Waller CF ，Pahl HL ，Zeiser R ，Daly RJ ，Brummer T ... -  《-》

Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development.

Burchert A ，Wang Y ，Cai D ，von Bubnoff N ，Paschka P ，Müller-Brüsselbach S ，Ottmann OG ，Duyster J ，Hochhaus A ，Neubauer A ... -  《LEUKEMIA》

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia.

Zeng X ，Zhao H ，Li Y ，Fan J ，Sun Y ，Wang S ，Wang Z ，Song P ，Ju D ... -  《-》