Activity of AT13387, a novel, non-ansamycin inhibitor of heat shock protein 90, against gastrointestinal stromal tumors (GIST).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 105-105 ◽  
Author(s):  
Daruka Mahadevan ◽  
Geoffrey Shapiro ◽  
Sandra E. Kurtin ◽  
James M. Cleary ◽  
John F. Lyons ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Heat Shock Protein 90 ◽  
Tumor Growth Inhibition ◽  
Resistance Mutations ◽  
Hsp90 Inhibition ◽  
Secondary Resistance ◽  
Imatinib Resistant

105 Background: AT13387 is a second-generation potent, novel non-ansamycin HSP90 inhibitor (Kd 0.71nM). The majority of GIST tumors are characterized by activating mutations of c-KIT, an HSP90 client protein. Secondary resistance mutations within c-KIT limit clinical responses to TKIs. The dependence of c-KIT and its mutated forms on HSP90 suggests that HSP90 inhibition may be a valuable treatment option for imatinib-sensitive and resistant clones. In vitro, AT13387 inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and imatinib-resistant (GIST430, GIST48) cell lines. In vivo, AT13387 demonstrated anti-tumor activity in the imatinib-sensitive (GIST-PSW) and imatinib-resistant (GIST430) xenograft models. Induction of HSP70, depletion of phospho-c-KIT and inhibition of c-KIT signaling were observed in both models. Combination treatment of imatinib and AT13387 in the GIST430 model was well tolerated and significantly enhanced tumor growth inhibition over either monotherapies. Methods: In a completed phase I study, AT13387 was administered IV over 1 hour twice weekly or weekly of a 28-day cycle in a standard 3+3 dose-escalation design. The primary endpoint was to determine the MTD; secondary endpoints included PK, PD, safety and tolerability. Results: The PK exposures were dose-dependent and linear. AT13387 was well tolerated on both schedules. DLTs included primarily G2 AEs of GI toxicities, fatigue and infusion site reactions. The once weekly RP2D was determined to be 260 mg/m2. HSP70 induction was 2–7 fold at higher doses. A total of 7 GIST subjects were enrolled. An objective and durable PR was observed in one subject and 2 SDs at 8, 7 and 11 months, respectively. The PR subject demonstrated molecular resistance to kinase inhibitor treatment in the c-KIT gene prior to initiation of AT13387 therapy in two resected lesions by harboring the same activating c-KIT deletion in exon 11 and two separate TKI resistance mutations in exon 17. Conclusions: Overall, these results suggest AT13387 is a promising agent in GIST, including TKI-resistant c-Kit positive GIST. AT13387 is currently being evaluated in combination with imatinib in an ongoing phase I/II study. Clinical trial information: NCT01294202.

scholarly journals Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole

2018 ◽  
Vol 10 ◽  
pp. 175883591878685 ◽  
Author(s):  
Hiroshi Umehara ◽  
Yoshimi Maekawa ◽  
Fumito Koizumi ◽  
Makiko Shimizu ◽  
Toshio Ota ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Drug Combination ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Her2 Positive ◽  
Grade 3 ◽  
Mcf 7

Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

Dasatinib (BMS-354825) Overcomes Multiple Mechanisms of Imatinib Resistance in Chronic Myeloid Leukemia (CML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1994-1994 ◽  
Author(s):  
Francis Y. Lee ◽  
Mei-Li Wen ◽  
Rajeev Bhide ◽  
Amy Camuso ◽  
Stephen Castenada ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitor ◽  
Leukemic Cell ◽  
K562 Cells ◽  
Src Family Kinases ◽  
Imatinib Resistance ◽  
Over Expression ◽  
Imatinib Resistant

Abstract Resistance to imatinib is a growing concern in CML, particularly in advanced disease. The most common cause of resistance is mutations in BCR-ABL, but other mechanisms have also been identified, including over-expression of BCR-ABL, activation of SRC family kinases and the P-glycoprotein (PGP) efflux pump (via MDR1 over-expression). Dasatinib (BMS-354825) is a novel, oral, multi-targeted tyrosine kinase inhibitor that targets BCR-ABL and SRC kinases. Dasatinib has 325-fold greater potency versus imatinib in cell lines transduced with wild-type BCR-ABL and is active against 18 out of 19 BCR-ABL mutations tested that confer imatinib resistance (Shah et al, Science305:399, 2004; O’Hare et al, Cancer Res65:4500–5, 2005), and preliminary results from a Phase I study show that it is well tolerated and has significant activity in imatinib-resistant patients in all phases of CML (Sawyers et al, J Clin Oncol23:565s, 2005; Talpaz et al, J Clin Oncol23:564s, 2005). We assessed the ability of dasatinib to overcome a variety of mechanisms of imatinib resistance. First, the leukemic-cell killing activity of dasatinib was tested in vitro in three human imatinib-resistant CML cell lines (K562/IM, MEG-01/IM and SUP-B15/IM). Based on IC50 values, dasatinib had >1000-fold more potent leukemic-cell killing activity compared with imatinib versus all three cell lines. Furthermore, in mice bearing K562/IM xenografts, dasatinib was curative at doses >5 mg/kg, while imatinib had little or no impact at doses as high as 150 mg/kg, its maximum tolerated dose. We determined that the MEG-01/IM and SUP-B15/IM cell lines carried BCR-ABL mutations known to confer imatinib resistance to imatinib clinically (Q252H and F359V, respectively). In K562/IM cells, BCR-ABL mutations or BCR-ABL over-expression were not detected, but the SRC family member FYN was over-expressed. PP2, a known inhibitor of SRC family kinases but not BCR-ABL, could reverse the imatinib resistance in these cells. Together, these data suggest that activation of FYN may be a cause of imatinib resistance in K562/IM. Based on cell proliferation IC50, we found that the anti-leukemic activity of dasatinib in K562/IM cells was 29-fold more potent compared with AMN107 (a tyrosine kinase inhibitor that inhibits BCR-ABL but not SRC family kinases). Given that the human serum protein binding of dasatinib, imatinib and AMN107 were 93, 92 and >99% respectively, the difference in potency between dasatinib and AMN107 in vivo may be far greater than the simple fold-difference in the in vitro IC50 values. Finally, in K562 cells over-expressing PGP (K562/ADM), we found that dasatinib was only 6-fold less active than in parental K562 cells. Because of the extreme potency of dasatinib in K562 cells, this reduced potency still afforded an IC50 of 3 nM, which is readily achievable in vivo. Indeed, in mice bearing K562/ADM xenografts, dasatinib was curative at 30 mg/kg, with significant anti-leukemic activity at 15 mg/kg. In conclusion, the rational design of dasatinib as a multi-targeted kinase inhibitor allows this agent to overcome a variety of mechanisms of resistance to imatinib in CML, including mechanisms that are not overcome by agents with a narrower spectrum of inhibition, such as AMN107. Dasatinib is currently in Phase II evaluation in imatinib-resistant/-intolerant patients in the ‘START’ program, and in Phase I evaluation in solid tumors.

KW-2449, a Novel Multi-Kinase Inhibitor, Suppresses the Growth of Imatinib-Resistant Ph+ Leukemia Including BCR-ABL/T315I Both in Vitro and in Vivo.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1640-1640 ◽  
Author(s):  
Yukimasa Shiotsu ◽  
Hitoshi Kiyoi ◽  
Ryohei Tanizaki ◽  
Yosuke Minami ◽  
Akihiro Abe ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Imatinib Treatment ◽  
Wild Type ◽  
Growth Inhibitory ◽  
Imatinib Resistant ◽  
Blast Cells ◽  
T315i Mutation

Abstract Background: KW-2449 is a multi-kinase inhibitor against FLT3, ABL and ABL/T315I and Aurora kinases with IC50 values of 0.007, 0.014, 0.004 and 0.048 micro mol/L, respectively. We reported a possible mode of action of KW-2449 with respect to its anti-leukemic effects on FLT3-mutated and FLT3-wild type leukemia cells via FLT3 and Aurora inhibition, respectively (1). Currently KW-2449 is being investigated in a Phase 1/2 study in patients with acute myeloid leukemia. In this report, we investigated the activity of KW-2449 or imatinib in imatinib-resistant leukemia with the T315I mutation. Methods and results: We evaluated the effects of KW-2449 in vitro and in vivo on imatinib-resistant Ph+ leukemia. While imatinib suppressed the growth of K562 (Ph+CML with wild-type BCR-ABL) and TCC-Y (Ph+ALL with wild-type BCR-ABL) with GI50 values of 0.20 and 0.18 micro mol/L, it had little inhibitory effects on TCC-Y/sr (Ph+ALL with BCR-ABL/T315I) with a GI50 value of 24 micro mol/L. On the other hand, KW-2449 showed equivalent growth inhibitory activities against K562, TCC-Y and TCC-Y/sr giving the GI50 values of 0.2–0.6 micro mol/L. In addition, KW-2449 showed potent growth inhibitory activity against IL-3 dependent cells transfected with BCR-ABL and BCR-ABL/T315I with GI50 values below 0.50 micro mol/L, whereas imatinib had no growth inhibition in BCR-ABL/T315I cells. When we examined the ABL-signaling pathway, imatinib had no effects on the expression of phosphorylated BCR-ABL (P-BCR-ABL) and STAT5 (P-STAT5), a key downstream signal molecules of BCR-ABL in TCC-Y/sr cells. Furthermore, no obvious apoptosis or cell cycle effects were observed in BCR-ABL/T315I cells after imatinib treatment. In addition, the exposure to KW-2449 induced reduction of P-BCR-ABL and P-STAT5 at 0.25 micro mol/L and induced G2/M arrest and apoptosis over the GI50 value (0.50–1.0 micro mol/L). These data provide the evidence that BCR-ABL inhibition at a lower concentration of KW-2449 modulates its signaling pathway and that Aurora inhibition at a higher concentration may play a critical role in the anti-proliferative effects in imatinib-resistant CML and Ph+ALL. To assess the anti-leukemia activity of KW-2449 in vivo, the SCID mice intravenously inoculated with TCC-Y/sr leukemia were orally treated with KW-2449 or imatinib. While KW-2449 prolonged the survival, imatinib treatment had no effects in this model. Furthermore, anti-proliferative activity of KW-2449 was examined in primary samples from blast crisis CML patients who had BCR-ABL/T315I mutation. After inoculation of blast cells into NOG mice, KW-2449 or imatinib treatment started. In this model, oral treatments with KW-2449 decreased peripheral copy number of BCR-ABL mRNA and CD45+ blast cells in the bone marrow, though imatinib treatment showed limited activity. Conclusion: KW-2449 demonstrated anti-leukemia activity against imatinib resistant leukemia both in vitro and in vivo. These results suggest that KW-2449 would be effective against imatinib-resistant CML or Ph+ALL because of its potent and unique kinase inhibition profile.

A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10023-10023 ◽  
Author(s):  
M. Von Mehren ◽  
P. Reichardt ◽  
P. G. Casali ◽  
J. Blay ◽  
M. Debiec-Rychter ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Clinical Activity ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11

10023 Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for > 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to > 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD > 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies. No significant financial relationships to disclose.

Inhibition and flare patterns of metabolic response to the heat shock protein 90 (Hsp90) inhibitor IPI-504 visualized by FDG-PET in patients (pts) with advanced gastrointestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3530-3530 ◽  
Author(s):  
A. D. Van den Abbeele ◽  
J. T. Yap ◽  
D. S. Grayzel ◽  
J. Walker ◽  
G. D. Demetri
Keyword(s):  
Fdg Pet ◽  
Kinase Inhibitor ◽  
Metabolic Response ◽  
Clinical Investigation ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Resistance Mutations ◽  
Hsp90 Inhibition ◽  
Standardized Uptake Values ◽  
Time Point

3530 Background: We have previously demonstrated the inhibition and rebound of GIST glycolytic metabolism with FDG-PET while pts were on or off TKI in prior trials of imatinib and sunitinib. We tested the same principle in a phase I trial of IPI-504, a novel potent inhibitor of Hsp90 (a chaperone for protein homeostasis) that results in selective destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. Methods: Twenty-one patients with metatastic and/or unresectable GIST following failure of prior therapy with TKI were treated with IPI-504. Serial FDG-PET imaging was performed at baseline, during the 1st cycle after at least 2 doses (C1, days 4–11, “ON”, n = 18), and at the end of the 10-day off-treatment period prior to the start of the 2nd cycle (C1, “OFF”, n = 20). A subset of 5 pts also had FDG-PET at the end of the 3rd cycle (C3, day 11, “ON”). Maximum standardized uptake values (SUVmax) were measured in up to 3 lesions/pt with the greatest FDG uptake, and the SUVmax of all lesions was summed at each time point. Percent change in the summed mean SUVmax was calculated at each time point relative to the previous scan. Temporal changes were evaluated in those pts showing more than a 10% decrease in SUVmax during C1 “ON” compared to baseline. Results: We observed a >10% reduction in SUVmax (mean = - 28%) during the 1st cycle (C1, “ON”) in 8/18 pts. All these pts showed an increase in SUVmax (mean = +29%) when off therapy (C1, “OFF”). Three of these 8 pts had a scan during cycle 3. All demonstrated a decrease in SUVmax (mean = -30%) while on the drug (C3, “ON”). Conclusion: These preliminary findings suggest that: (1) tumor metabolic response as measured with FDG-PET parallels the intermittent pattern of IPI-504 administration in this study as early as after the 2nd dose administration; and, (2) IPI-504 has a rapid downstream effect on glucose metabolism similar to that observed with TKIs despite the very different mechanism of action of IPI-504. The pattern of response to Hsp90 inhibition seen in this heavily pretreated population strongly supports further clinical investigation. No significant financial relationships to disclose.

Mineralocorticoid receptor degradation is promoted by Hsp90 inhibition and the ubiquitin-protein ligase CHIP

2010 ◽  
Vol 299 (6) ◽  
pp. F1462-F1472 ◽  
Author(s):  
Nourdine Faresse ◽  
Dorothée Ruffieux-Daidie ◽  
Mélanie Salamin ◽  
Celso E. Gomez-Sanchez ◽  
Olivier Staub
Keyword(s):  
Mineralocorticoid Receptor ◽  
Nuclear Translocation ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibition ◽  
Interacting Protein ◽  
Ubiquitin Protein Ligase ◽  
The Stability ◽  
Benzoquinone Ansamycin

The mineralocorticoid receptor (MR) plays a crucial role in the regulation of Na+ balance and blood pressure, as evidenced by gain of function mutations in the MR of hypertensive families. In the kidney, aldosterone binds to the MR, induces its nuclear translocation, and promotes a transcriptional program leading to increased transepithelial Na+ transport via the epithelial Na+ channel. In the unliganded state, MR is localized in the cytosol and part of a multiprotein complex, including heat shock protein 90 (Hsp90), which keeps it ligand-binding competent. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic that binds to Hsp90 and alters its function. We investigated whether 17-AAG affects the stability and transcriptional activity of MR and consequently Na+ reabsorption by renal cells. 17-AAG treatment lead to reduction of MR protein level in epithelial cells in vitro and in vivo, thereby interfering with aldosterone-dependent transcription. Moreover, 17-AAG inhibited aldosterone-induced Na+ transport, possibly by interfering with MR availability for the ligand. Finally, we identified the ubiquitin-protein ligase, COOH terminus of Hsp70-interacting protein, as a novel partner of the cytosolic MR, which is responsible for its polyubiquitylation and proteasomal degradation in presence of 17-AAG. In conclusion, 17-AAG may represent a novel pharmacological tool to interfere with Na+ reabsorption and hypertension.

scholarly journals Modulated Electro-Hyperthermia Resolves Radioresistance of Panc1 Pancreas Adenocarcinoma and Promotes DNA Damage and Apoptosis In Vitro

2020 ◽  
Vol 21 (14) ◽  
pp. 5100 ◽  
Author(s):  
Gertrud Forika ◽  
Andrea Balogh ◽  
Tamas Vancsik ◽  
Attila Zalatnai ◽  
Gabor Petovari ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chromatin Condensation ◽  
Annexin V ◽  
Therapy Resistance ◽  
In Vivo Model ◽  
Tumor Growth Inhibition ◽  
Dna Double Strand Breaks ◽  
Cell Fractions

The poor outcome of pancreas ductal adenocarcinomas (PDAC) is frequently linked to therapy resistance. Modulated electro-hyperthermia (mEHT) generated by 13.56 MHz capacitive radiofrequency can induce direct tumor damage and promote chemo- and radiotherapy. Here, we tested the effect of mEHT either alone or in combination with radiotherapy using an in vivo model of Panc1, a KRAS and TP53 mutant, radioresistant PDAC cell line. A single mEHT shot of 60 min induced ~50% loss of viable cells and morphological signs of apoptosis including chromatin condensation, nuclear shrinkage and apoptotic bodies. Most mEHT treatment related effects exceeded those of radiotherapy, and these were further amplified after combining the two modalities. Treatment related apoptosis was confirmed by a significantly elevated number of annexin V single-positive and cleaved/activated caspase-3 positive tumor cells, as well as sub-G1-phase tumor cell fractions. mEHT and mEHT+radioterapy caused the moderate accumulation of γH2AX positive nuclear foci, indicating DNA double-strand breaks and upregulation of the cyclin dependent kinase inhibitor p21waf1 besides the downregulation of Akt signaling. A clonogenic assay revealed that both mono- and combined treatments affected the tumor progenitor/stem cell populations too. In conclusion, mEHT treatment can contribute to tumor growth inhibition and apoptosis induction and resolve radioresistance of Panc1 PDAC cells.

Hematologic and Cytogenetic Responses in Imatinib-Resistant Accelerated and Blast Phase Chronic Myeloid Leukemia (CML) Patients Treated with the Dual SRC/ABL Kinase Inhibitor BMS-354825: Results from a Phase I Dose Escalation Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 20-20 ◽  
Author(s):  
Moshe Talpaz ◽  
Hagop Kantarjian ◽  
Neil P. Shah ◽  
Nicholas Donato ◽  
John Nicoll ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Cytogenetic Response ◽  
Blast Phase ◽  
Abl Kinase ◽  
Hematologic Response ◽  
Imatinib Resistant ◽  
A Minor

Abstract BMS-354825 is a novel, orally available, dual SRC/ABL kinase inhibitor with 100-fold greater potency to inhibit BCR-ABL in vitro than imatinib and has in vitro and in vivo preclinical activity against 14 of 15 imatinib resistant BCR-ABL mutants (Shah et al, Science, 305:399, 2004). Here we report the phase I clinical results of BMS-354825 in Philadelphia chromosome positive accelerated phase (AP) and blast phase (BP) CML patients who had hematologic progression or intolerance while being treated with imatinib. As of Aug 6, 2004, 17 patients (6 with AP; 11 with BP) have been treated in 3 cohorts with doses ranging from 35 mg BID (1 patient) to 70 mg BID of BMS-354825. BMS-354825 is rapidly absorbed with peak concentrations achieved within 2 hours and a terminal phase half-life of about 5 hours. Consistent, rapid and sustained inhibition of LYN kinase, a member of the SRC family of tyrosine kinases, has been demonstrated. Of the 11 BP patients, 7 have had hematologic response: 3 complete hematologic response (CHR), 2 ‘no evidence of leukemia’ (NEL), and 2 ‘return to chronic phase’ (RTC). Three additional patients have had significant hematologic improvement despite being on treatment only a short period of time (10–23 days). One patient with extramedullary disease was stable. Cytogenetic data is available for 8 of the 11 BP patients. Four patients had major cytogenetic response, 2 patients had a minor cytogenetic response and 2 patients had no response. BCR-ABL mutation data is available for 2 patients: one patient did not have a mutation and one patient who had a non-sustained CHR was found to have a E355G mutation. Three of 6 AP patients have had hematologic response: 2 CHRs and 1 NEL. Two patients are too early to assess. One patient demonstrated resistance to BMS-354825 due to a T315I mutation in BCR-ABL found in 8 of 10 clones. This mutation confers resistance to BMS-354825 in preclinical studies. BCR-ABL mutation status is available for 3 additional AP patients: 2 patients had no mutations identified and 1 patient in CHR had M351T/A imatinib-resistant mutations. Of 3 patients for whom early cytogenetic data is available, 1 had a minor cytogenetic response (40% Ph+). To date BMS-354825 has been very well tolerated. Two patients in blast phase had evidence of mild tumor lysis syndrome. Dose escalation is continuing and phase II studies in chronic, accelerated and blast phase CML are currently being initiated. Further studies are required to establish LYN’s potential role in imatinib-resistant CML. The clinical data demonstrate that BMS-354825 can frequently override imatinib resistance in advanced CML, and provide compelling evidence supporting the safety and efficacy of BMS-354825 in imatinib-resistant accelerated and blast phase CML.

Molecular Analysis of Dasatinib Resistance Mechanisms in CML Patients Identifies Novel BCR-ABL Mutations Predicted To Retain Sensitivity to Imatinib: Rationale for Combination Tyrosine Kinase Inhibitor Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1093-1093 ◽  
Author(s):  
Neil P. Shah ◽  
John M. Nicoll ◽  
Susan Branford ◽  
Timothy P. Hughes ◽  
Ronald L. Paquette ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Kinase Domain ◽  
Saturation Mutagenesis ◽  
Imatinib Resistant ◽  
T315i Mutation ◽  
Resistant Mutation ◽  
Phase I And Ii

Abstract Point mutations within the BCR-ABL kinase domain represent the most common mechanism of resistance to imatinib in patients with CML. Preclinical studies have shown that dasatinib (BMS-354825) is effective at inhibiting the kinase activity of imatinib-resistant BCR-ABL mutants with the notable exception of the T315I mutation, which remains highly resistant to imatinib, dasatinib, and AMN107 (Gorre et al, Science 2001; Shah et al, Science 2004; Weisberg et al, Cancer Cell, 2005). Clinical data from Phase I and II studies of dasatinib in CML confirms the in vitro findings. Each of three imatinib-resistant patients bearing the T315I mutation (CP=1; AP=2) did not achieve objective hematologic or cytogenetic responses during treatment with dasatanib on a Phase I study. Additionally, each of two phase II patients with the T315I mutation (CP=1; LBC=1) treated at UCLA showed no evidence of objective response. We have also detected the T315I mutation in each of two cases of acquired resistance in a phase II (LBC =2) study, and in seven of nine patients with acquired resistance to dasatinib in phase I and II studies (CP=1; MBC=3; LBC=2; Ph+ ALL=1). Notably, we detected a novel BCR-ABL mutation, T315A, in one of the two patients who relapsed without a detectable T315I mutation. The patient is a 53 year-old female whose chronic phase CML had progressed to myeloid blast phase while being treated with imatinib. The imatinib-resistant mutation M244V was identified prior to dasatinib treatment. The patient achieved a major hematologic response (<5% blasts with partial recovery of peripheral blood counts) on dasatinib 90 mg orally given twice daily, but relapsed with MBC after six months. Sequence analysis of the BCR-ABL kinase domain at the time of relapse revealed the presence of the imatinib-resistant mutation M244V as well as the novel mutation T315A. This finding is of particular interest because T315A and several other novel BCR-ABL mutations were recently recovered in a saturation mutagenesis study designed to define potential mechanisms of dasatinib resistance. Remarkably, many of these mutations retain sensitivity to imatinib in vitro (Burgess et al, PNAS, 2005). Through periodic molecular monitoring of other dasatinib-treated patients, we have identified a second novel BCR-ABL mutant, F317I, that developed in an imatinib-resistant CP patient after 9 months of treatment. Similar to T315A, F317I was isolated in the saturation mutagenesis screen for dasatinib resistance and is predicted to retain sensitivity to imatinib. Taken together, our findings implicate the T315I mutation as the principle mechanism of resistance to dasatinib, but more importantly, strongly support the use for combination kinase inhibitor therapy in CML to prevent emergence of drug resistant clones. A phase I trial to assess the safety of combining imatinib with dasatinib is planned.

scholarly journals Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors

2019 ◽  
Vol 11 ◽  
pp. 175883591984975
Author(s):  
Feiyang Liu ◽  
Fengming Zou ◽  
Cheng Chen ◽  
Kailin Yu ◽  
Xiaochuan Liu ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Binding Modes ◽  
Primary Cells ◽  
Resistance Mutations ◽  
Preclinical Models ◽  
Gain Of Function ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Imatinib Resistant

Background: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells. Methods: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib. Results: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models. Conclusion: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.

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