Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase

Rabindran, Sridhar K.; Discafani, Carolyn; Rosfjord, Edward; Baxter, Michelle; Floyd, M. Brawner; Golas, Jonathan; Hallett, William; Johnson, Bernard; Nilakantan, Ramaswamy; Overbeek, Elsebe; Reich, Marvin F.; Shen, Ru; Shi, Xianglin; Tsou, Hwei‐Ru; Wang, Yufen; Wissner, Allan

doi:10.1158/0008-5472.can-03-2868

Cited by 567 publications

(457 citation statements)

References 28 publications

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“…To more directly assess inhibition of BCR-ABL enzymatic activity in cells, we measured BCR-ABL autophosphorylation. BIRB-796 inhibited BCR-ABL(T315I) autophosphorylation in Ba͞F3 cells with an IC 50 value of 1-2 M (Fig. 1A), consistent with the results of the cell proliferation assay and the in vitro activity assay (see above), and confirming that this compound is an inhibitor of ABL(T315I).…”

Section: Methodssupporting

confidence: 86%

“…1A), consistent with the results of the cell proliferation assay and the in vitro activity assay (see above), and confirming that this compound is an inhibitor of ABL(T315I). The IC 50 for inhibition of BCR-ABL(T315I) autophosphorylation in Ba͞F3 cells by VX-680 was Ϸ5 M (Fig. 1B), significantly higher than the binding constant (Table 1) and the IC 50 for inhibition of ABL enzymatic activity measured in vitro.…”

Section: Methodsmentioning

confidence: 74%

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

Carter

Wodicka

Shah

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

521

390

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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 KIT͞FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D͞T670I) 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 gefitiniband erlotinib-resistant EGFR(L858R͞T790M) 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 gefitinib͞ 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 nextgeneration drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy. drug resistance ͉ gatekeeper mutation ͉ kinase inhibitor

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Section: Methodssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 74%

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

Carter

Wodicka

Shah

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

521

390

View full text Add to dashboard Cite

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“…4 A-C). The mice were then treated with continued doxycycline and with daily oral administration of placebo vehicle, erlotinib (a reversible EGFR inhibitor), or HKI-272 (an irreversible EGFR͞ ERB2 inhibitor) at 50 mg͞kg, a concentration that has been shown effective in xenograft models with lung cancer cells or breast cancer cells (27,28). As expected, after 7 days of placebo treatment, the number and size of lung tumors increased (Fig.…”

Section: Resultssupporting

confidence: 55%

“…Irreversible inhibitors of EGFR such as CL-387,785 and HKI-272 are believed to block the kinase enzymatic function by covalently binding to Cys-797 residue in the EGFR (corresponding to Cys-530 in the EGFRvIII truncated protein) (28,34). We generated the C530S mutation in the background of the EGFRvIII mutation and introduced EGFRvIII-C530S into Ba͞F3 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

Zhao

Yuza

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

233

175

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The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3͞56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0͞123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba͞F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.irreversible inhibitor ͉ lung cancer ͉ lung squamous cell carcinoma E pidermal growth factor receptor (EGFR) is commonly overexpressed and mutated in many human malignancies and is often associated with aggressive phenotypes (1-3). Before the recent discovery of the somatic mutations in the EGFR kinase domain (4-8) in non-small cell lung cancers (NSCLC), deletions of the extracellular domain were considered the most frequent EGFR mutations in the different tumor types (9-13). These deletions have an activating effect on the receptor, giving cells expressing these truncated receptors a proliferative advantage. The most common truncated receptor is the variant III EGFR deletion mutant (EGFRvIII, delta 801EGFR, del2-7 EGFR), containing an inframe deletion of exons 2-7 (801 bp) from the extracellular domain, initially characterized at the genomic level in glioblastoma.Studies using immunohistochemical assays with EGFRvIII mutant-specific antibodies suggest that this mutation is present in multiple other tumor types, including NSCLC (10,11,14). However, because of EGFR's large and complex genomic structure (28 exons spanning Ϸ190 kb) and its large intron 1 (123 kb) where genomic deletions frequently occur, it has been difficult to assess and verify the existence of the EGFRvIII mutations at the genomic level. EGFRvIII mutations have been well demonstrated in glioblastoma, where they are present in Ͼ50% of glioblastomas with amplification of EGFR gene locus (12, 15, 16), but no genomic evidence for the existence of EGFRvIII mutations has been reported in NSCLC. Furthermore, the role of EGFRvIII mutation in the potential pathogenesis of NSCLC is unclear.Here, we report that the EGFRvIII mut...

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“…inhibits EGFR and HER2 kinase activity in vitro BIBW2992, an anilino-quinazoline designed as an irreversible, dual EGFR/HER2 inhibitor, possesses a functional Michael acceptor group similar to the one found in the quinoline-derived irreversible EGFR inhibitors EKB-569 and HKI-272, allowing covalent modification of the ATP-binding site of the kinase domains of EGFR (Cys 773) and HER2 (Cys 805) (Rabindran et al, 2004;Eskens et al, 2008). In cell-free in vitro kinase assays, BIBW2992 shows potent activity against wild-type and mutant forms of EGFR and HER2, similar to gefitinib in potency for L858R EGFR, but about 100-fold more active against the gefitinibresistant L858R-T790M EGFR double mutant, with an IC 50 of 10 nM (Table 1).…”

Section: Bibw2992mentioning

confidence: 99%

BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models

et al. 2008

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Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to firstgeneration EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.

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Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase

Cited by 567 publications

References 28 publications

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

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

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models

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