Imatinib-resistant Gastrointestinal Tumors Research Articles

Sunitinib Reduces Acute Myeloid Leukemia Clonogenic Cells <i>in Vitro</i> and Has Potent Inhibitory Effect on Sorted AML ALDH+ Cells

Sunitinib is an orally administered, multi-target tyrosine kinase inhibitor that has been approved by the FDA for the treatment of renal cell carcinoma and imatinib resistant gastro-intestinal tumors. Anti-leukemic activity of sunitinib has been examined in early clinical trials with limited success. However, recent trials on acute myeloid leukemia (AML) patients carrying FLT3 mutations have shown promising results. Effects of sunitinib on leukemic clonogenic cells and potential leukemic stem cells have not been examined so far. We analyzed the anti-proliferative and apoptotic properties of sunitinib on AML-derived cell lines. We also tested the effect of sunitinib on AML patient derived clonogenic cells (AML-CFC), as well as flow-sorted potential leukemic progenitors. Peripheral blood or bone marrow samples were obtained from newly diagnosed AML patients and flow sorted for CD34+ CD133+ or ALDH+ cells. Umbilical cord blood derived CD34+ cells were used as normal controls. Sunitinib induced growth arrest and apoptosis in AML derived cell lines. In addition, 7 μM sunitinib induced 75% reduction of AML-CFC as compared to DMSO treated control (±6.79%; n = 4). In contrast, 7 μM sunitinib treatment of umbilical cord blood derived normal CD34+ cells showed 29% reduction in AML-CFC (±6.77%; n = 5). Treatment of ALDH+ cells sorted from 2 AML cases and CD34+ CD133+ cells from one patient showed reduction of AML-CFC on treatment with sunitinib. Our study highlighted a potent anti-proliferative and proapoptotic effect of sunitinib on AML cell lines, AML patient derived clonogenic cells and potential leukemic stem cells.

Chloroquine as a promising adjuvant chemotherapy together with sunitinib

Chloroquine - a clinically available and cheap antimalarial drug - might have potential usefulness as adjuvant chemotherapy when combined with sunitinib, reports a preclinical study recently published online in Chemico-biological Interactions . Just few years after its FDA approval to be used in renal cell carcinoma, imatinib resistant gastrointestinal tumor and pancreatic neuroendocrine tumor, increasing studies shed light on the limited clinical efficacy of sunitinib as well as rapid development of resistant cells when used as monotherapy presumably through lysosomal sequestration. Abdel-Aziz and her colleagues now showed that chloroquine augments sunitinib anticancer activity in vitro human cancer cell lines of breast, colorectal, cervical, laryngeal, liver and prostate origin and in vivo in murine Ehrlich ascites carcinoma tumor model. Furthermore, Abdel-Aziz and her colleagues showed that chloroquine interrupts autophagic flux which was induced by sunitinib. They noted that chloroquine when combined with sunitinib showed further activation of apoptosis in cancer cells. The observed synergy was associated with increased nitric oxide level and reduced reactive oxygen species levels. The present findings warrant further studies to explore the safety profile of the combination regimen and its clinical usefulness in vivo and then controlled clinical trials.

Sunitinib effectively reduces clonogenic acute myeloid leukemia cells in vitro

Background Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by enhanced proliferation and block in differentiation of immature myeloid cells. AML pathogenesis is attributed to several recurrent chromosomal abnormalities in nearly half of the AML cases while the rest of the AML cases show at least one or more molecular abnormalities. Activating mutations and/or high expression of receptor tyrosine kinase (RTK) family members (FLT3, cKIT) have been well documented in AML. Specific RTK inhibitors (TKI) have been developed for targeted therapy of AML and many are currently under study [1]. Sunitinib is a potent multi-TKI that has been FDA approved for renal carcinoma and imatinib resistant gastro intestinal tumors. Although some studies show the effect of Sunitinib on AML cell line growth, there has been no investigation of its effect on AML clonogenic cells [2]. In the current study, we investigated the effect of Sunitinib on clonogenic AML cells and normal hematopoietic progenitors in vitro.

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.