Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway.

@article{Kurosu2009SorafenibIA,
  title={Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway.},
  author={Tetsuya Kurosu and Manabu Ohki and Nan Wu and Hiroyuki Kagechika and Osamu Miura},
  journal={Cancer research},
  year={2009},
  volume={69 9},
  pages={
          3927-36
        }
}
Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than… 
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Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway
TLDR
It is demonstrated that nutlin-3, an inhibitor of Mdm2, inhibits proliferation and induces apoptosis more effectively in BCR/ABL-driven Ton.B210 cells than in those driven by IL-3.
The Role of Mitochondrial DNA Damage and Repair in the Resistance of BCR/ABL-Expressing Cells to Tyrosine Kinase Inhibitors
TLDR
Mitochondria and mitochondria-associated molecules and pathways may be attractive targets to overcome TKI resistance in CML.
PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positive leukemia cells
TLDR
Overexpression of PECAM-1 in BCR/ABL-expressing cells, including K562 human leukemia cells, enhanced cell adhesion and partially inhibited imatinib-induced apoptosis involving mitochondria depolarization and caspase-3 cleavage, at least partly, in an ITIM-independent manner.
Small GTPase RAB45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells.
TLDR
The results identify a new signaling molecule involved in BCR-ABL modulation of apoptosis and suggest that RAB45 induction strategies may have therapeutic utility in patients with CML.
Sorafenib Inhibits Cell Migration and Stroma-Mediated Bortezomib Resistance by Interfering B-cell Receptor Signaling and Protein Translation in Mantle Cell Lymphoma
TLDR
It is shown for the first time that sorafenib interferes with BCR signaling, protein translation and modulates the microenvironment prosurvival signals in MCL, suggesting that sorAFenib, alone or in combination with bortezomib, may represent a promising approach to treat patients with MCL.
Inhibition of the PI3K/Akt/GSK3 Pathway Downstream of BCR/ABL, Jak2-V617F, or FLT3-ITD Downregulates DNA Damage-Induced Chk1 Activation as Well as G2/M Arrest and Prominently Enhances Induction of Apoptosis
TLDR
The results shed light on the molecular mechanisms for chemoresistance of hematological malignancies and provide a rationale for the combined treatment with chemotherapy and the tyrosine kinase or PI3K/Akt pathway inhibitors against these diseases.
Down regulation of Chk1 by p53 plays a role in synergistic induction of apoptosis by chemotherapeutics and inhibitors for Jak2 or BCR/ABL in hematopoietic cells
TLDR
It is demonstrated here that a dominant negative mutant of p53, p53-DD, increases Chk1-mediated G2/M checkpoint activation induced by chemotherapeutics and protects it from down regulation by inhibition of Jak2, BCR/ABL, or the PI3K/Akt pathway in hematopoietic model cell lines 32D and BaF3.
Contribution of BCR–ABL‐independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells
TLDR
It is concluded that the BCR–ABL‐independent activation of ERK1/2 contributes to imatinib resistance in K562/R cells, and that ERK 1/2 could be a target for the treatment of CML patients whose imatinIB resistance is due to this mechanism.
Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process.
TLDR
Combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML, according to studies in a xenograft mouse model.
Inhibition of the STAT5/Pim Kinase Axis Enhances Cytotoxic Effects of Proteasome Inhibitors on FLT3-ITD–Positive AML Cells by Cooperatively Inhibiting the mTORC1/4EBP1/S6K/Mcl-1 Pathway1
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