Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells.
By C. Bellodi, M. Lidonnici, A. Hamilton, G. Helgason, A. R. Soliera, M. Ronchetti, Sara Galavotti, K. W. Young, Tommaso Selmi, R. Yacobi and 54 more. Journal of Clinical Investigation, 2009
605 citations recorded by the source corpus.
Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.
Subfields: Genetics, Hematology, Organic Chemistry
View Paper: https://www.semanticscholar.org/paper/87bd757e6a66980876db4324f2a6dadb51efbddf
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Citations in the corpus
- Pancreatic cancers require autophagy for tumor growth. (2011, positive): “Cooperation of autophagy inhibition with chemotherapy has also been observed in leukemia (Carew et al. 2007; Bellodi et al. 2009), and may reflect the upregulation of autophagy as a possible survival mechanism in response to chemotherapeutic agents (Hippert et al.”
- Autophagy as a target for anticancer therapy (2011, background): “Of interest, findings from several preclinical studies showed that autophagy might underlie resistance to imatinib and dasatinib in chronic myeloid leukemia (CML)”
- Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma (2011, background): “Interestingly, imatinib’s induction of autophagy seems to decrease its effectiveness in chronic myelogenous leukemia (CML) and blocking of autophagy lead to increased apoptotic cell death [142].”
- Apoptosis, autophagy, necroptosis, and cancer metastasis (2015, background): “Recently, autophagy has been shown to be a critical factor for CSC survival and drug resistance [107,108].”