Opportunities and challenges in the development of kinase inhibitor therapy for cancer

Sawyers, Charles L.

doi:10.1101/gad.1152403

Cited by 162 publications

(104 citation statements)

References 88 publications

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“…Recent efforts to sequence the kinome in a broad range of tumors have expanded the list of oncogenic kinase mutations in human cancers (17)(18)(19)(20)(21). The likelihood of clinical benefit for patients whose tumors bear such mutations is very high when treated with appropriate inhibitors, but so is the risk of acquired resistance (22). Although the number of such diseases for which the molecular basis for resistance has been resolved is small (CML and gastrointestinal stromal tumor), the mechanism is consistent: selection for tumor subclones bearing secondary kinase domain mutations that block drug action.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance

Burgess

Skaggs²,

Shah³

et al. 2005

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

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Structural studies suggest that most point mutations in the BCR-ABL kinase domain cause resistance to the ABL kinase inhibitor imatinib by impairing the flexibility of the kinase domain, restricting its ability to adopt the inactive conformation required for optimal imatinib binding, rather than by directly interfering with drug contact residues. BMS-354825, currently in clinical development for imatinib-resistant chronic myelogenous leukemia, is a dual SRC͞ABL kinase inhibitor that binds ABL in both the active and inactive conformation. To examine the potential role of conformational binding properties in drug resistance, we mapped the mutations in BCR-ABL capable of conferring resistance to BMS-354825. Through saturation mutagenesis, we identified 10 such BCR-ABL mutations, 8 of which occurred at drug contact residues. Some mutants were unique to BMS-354825, whereas others also conferred imatinib resistance. Remarkably, the identity of the amino acid substitution at either of two contact residues differentially affects sensitivity to imatinib or BMS-354825. The combination of imatinib plus BMS-354825 greatly reduced the recovery of drug-resistant clones. Our findings provide further rationale for considering kinase conformation in the design of kinase inhibitors against cancer targets.BMS-354825 ͉ chronic myeloid leukemia ͉ imatinib ͉ mutagenesis

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance

Burgess

Skaggs²,

Shah³

et al. 2005

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

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291

221

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“…Kinase inhibitors, such as imatinib mesylate (Gleevec), have been shown to be effective in a variety of tumor types and are rapidly becoming accepted as cancer therapeutics (Sawyers, 2003). BAY 43-9006 is a novel investigational cancer therapeutic that potently inhibits the serine/threonine kinases RAF-1 and wildtype and V600E mutant BRAF, as well as several receptor tyrosine kinases (Lyons et al, 2001;Lowinger et al, 2002;Karasarides et al, 2004;Wilhelm et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

et al. 2005

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Thyroid cancer poses a significant clinical challenge, and our understanding of its pathogenesis is incomplete. To gain insight into the pathogenesis of papillary thyroid carcinoma, transcriptional profiles of four normal thyroids and 51 papillary carcinomas (PCs) were generated using DNA microarrays. The tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS. Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status. By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups. Using small numbers of genes, a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations. One tumor without a detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis. Among the mutation-specific expression signatures were genes whose differential expression was a direct consequence of the mutation, as well as genes involved in a variety of biological processes including immune response and signal transduction. Expression of one mutationspecific differentially expressed gene, TPO, was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors. The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors, a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations.

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“…Overexpression or activating mutations involving elements of the ERK pathway occur in the majority of cancer patients and are often associated with poor prognosis (6,7). Further support for their clinical relevance comes from the responses that are seen in patients treated with a range of drugs or monoclonal antibodies that inhibit these molecules (8)(9)(10). The ERK pathway has many inputs that converge on raf kinase and many potentially important effectors that are downstream from ERK.…”

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confidence: 99%

Pharmacodynamic monitoring of BAY 43‐9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells

Tong

Chow

Hedley

2006

Cytometry Part B Clinical

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Opportunities and challenges in the development of kinase inhibitor therapy for cancer

Cited by 162 publications

References 88 publications

Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance

Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance

Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

Pharmacodynamic monitoring of BAY 43‐9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells

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