P13K pathway mutations in cancer

Patent metadata

Field	Value
Publication number	US-9580750-B2
Application number	US-92086006-A
Country	US
Kind code	B2
Filing date	May 23, 2006
Priority date	May 23, 2005
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

Given the important role of protein kinases in pathways affecting cellular growth and invasion, we have analyzed 340 serine/threonine kinases for genetic mutations in colorectal cancers. Mutations in eight genes were identified, including three members of the phosphatidylinositol-3-kinase (PI3K) pathway; the alterations in the latter genes each occurred in different tumors and did not overlap with mutations in PIK3CA or other non-serine-threonine kinase (STK) members of the PI3K pathway, suggesting that mutations in any of these genes had equivalent tumorigenic effects. These data demonstrate that the PI3K pathway is a major target for mutational activation in colorectal cancers and provide new opportunities for therapeutic intervention.

First claim

We claim:

1. A method comprising:
performing an assay on a sample of a cancer tissue of a human that has:
a methionine codon at codon 354 or a glutamine codon at codon 527 of protein kinase family member gene PDK1, or
a glycine codon at codon 302 or a histidine codon at codon 371 of protein kinase family member gene AKT2,

wherein the assay tests codon 354 or codon 527 of the PDK1 gene, residue 354 or residue 527 of the PDK1 protein kinase, codon 302 or codon 371 of the AKT2 gene, or residue 302 or 371 of AKT2 protein kinase and detects said residue.

2. The method of claim 1 wherein the cancer tissue is a colorectal cancer tissue.

3. The method of claim 1 wherein the assay tests protein kinase family member PDK1.

4. The method of claim 1 wherein the assay tests protein kinase family member AKT2.

5. The method of claim 1 further comprising the step of placing the human in an arm of a clinical trial.

6. The method of claim 1 wherein the assay is selected from the group consisting of: nucleotide sequencing, allele specific hybridization, allele specific amplification, primer extension, and mutant specific antibody binding.

7. A method comprising:
testing a sample of a colorectal cancer tissue of a human that contains an amplified AKT2 gene for amount of
AKT2 gene in the colorectal cancer tissue relative to amount of a genomic control in said colorectal cancer tissue.

8. The method of claim 7 wherein amplification of at least 5-fold is determined.

9. The method of claim 7 further comprising the step of placing the human in an arm of a clinical trial.

10. The method of claim 7 wherein the genomic control is a chromosome 19 reference region.

11. The method of claim 7 wherein the testing employs an assay selected from the group consisting of: quantitative polymerase chain reaction, fluorescence in situ hybridization, digital karyotyping, and a kinase phosphorylation assay.

12. A method comprising:
hybridizing nucleic acids of a sample of a cancer tissue of a human that has
a methionine codon at codon 354 or a glutamine codon at codon 527 of protein kinase family member gene PDK1, or
a glycine codon at codon 302 or a histidine codon at codon 371 of protein kinase family member gene AKT2,

with an oligonucleotide that hybridizes to said codon in the protein kinase family member gene; and
detecting hybridization, or extending the oligonucleotide, or amplifying by extending the oligonucleotide.

13. A method comprising:
contacting proteins in a sample of a cancer tissue of a human that has
a methionine residue at residue 354 or a glutamine residue at residue 527 of protein kinase family member PDK1, or
a glycine residue at residue 302 or a histidine residue at residue 371 of protein kinase family member AKT2,

with an antibody that is specific for said residue in the protein kinase family member, and
detecting binding of the antibody to proteins in the sample.

Assignees

• Parsons Donald William
• Wang Tian-Li
• Samuels Yardena
• Bardelli Alberto
• Lengauer Christopher
• Velculescu Victor
• Kinzler Kenneth W
• Vogelstein Bert
• Univ Johns Hopkins

Inventors

• Parsons Donald William
• Wang Tian-Li
• Samuels Yardena
• Bardelli Alberto
• Lengauer Christopher
• Velculescu Victor
• Kinzler Kenneth W
• Vogelstein Bert

Classifications

• G01N33/57535

  of the large intestine, e.g. colon, rectum or anus · CPC title

• G01N33/5044

  involving specific cell types · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q1/485

  involving kinase · CPC title

• C12Q2600/136

  Screening for pharmacological compounds · CPC title