Methods for diagnosing and treating cancer by means of the expression status and mutational status of NRF2 and downstream target genes of said gene

Patent metadata

Field	Value
Publication number	US-11066709-B2
Application number	US-201816230223-A
Country	US
Kind code	B2
Filing date	Dec 21, 2018
Priority date	Jul 8, 2016
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

The invention provides methods of identifying a subject having cancer, such as lung cancer, by analyzing expression levels of one or more NRF2 splice variants or NRF2 target genes. The invention also provides methods of treating cancer in a subject with a NRF2 pathway antagonist, wherein the subject expresses one or more NRF2 splice variants or overexpresses one or more NRF2 target genes.

First claim

The invention claimed is:

1. A method of treating a subject having a cancer, the method comprising:
(a) determining the mRNA expression of NRF2 in a sample obtained from the subject, wherein the subject expresses NRF2 comprising an exon 2-deleted NRF2 splice variant, and wherein the presence of the exon 2-deleted NRF2 splice variant identifies the subject as likely to respond to a NRF2 pathway antagonist; and
(b) administering to the subject a therapeutically effective amount of a NRF2 pathway antagonist.

2. The method of claim 1 , wherein the NRF2 further comprises an exon 3-deleted NRF2 splice variant.

3. The method of claim 1 , wherein the mRNA expression is determined by RNA-seq, PCR, RT-PCR, gene expression profiling, serial analysis of gene expression, or microarray analysis.

4. The method of claim 1 , wherein the NRF2 pathway antagonist is a CREB antagonist, a CREB Binding Protein (CBP) antagonist, a Maf antagonist, an activating transcription factor 4 (ATF4) antagonist, a protein kinase C (PKC) antagonist, a Jun antagonist, a glucocorticoid receptor antagonist, a UbcM2 antagonist, a HACE1 antagonist, a c-Myc agonist, a SUMO agonist, a KEAP1 agonist, a CUL3 agonist, or a retinoic acid receptor a (RARα) agonist.

5. The method of claim 1 , wherein the sample obtained from the subject is a tumor sample.

6. The method of claim 5 , wherein the tumor sample is from a biopsy.

7. The method of claim 1 , wherein the subject has a lung cancer or a head and neck cancer.

8. The method of claim 7 , wherein the head and neck cancer is a squamous head and neck cancer.

9. The method of claim 7 , wherein the lung cancer is a non-small cell lung cancer (NSCLC).

10. The method of claim 9 , wherein the NSCLC is a squamous NSCLC.

11. A method of treating a subject having a cancer, the method comprising:
(a) determining a DNA sequence of NRF2 in a sample obtained from the subject, wherein the subject has a DNA sequence of NRF2 comprising a deletion of exon 2 that encodes an exon 2-deleted NRF2 splice variant, and wherein the presence of the deletion identifies the subject as likely to respond to a NRF2 pathway antagonist; and
(b) administering to the subject a therapeutically effective amount of a NRF2 pathway antagonist.

12. The method of claim 11 , wherein the subject has a DNA sequence of NRF2 further comprising a deletion of exon 3 that encodes an exon 3-deleted NRF2 splice variant.

13. The method of claim 11 , wherein the DNA sequence is determined by PCR, exome-seq, microarray analysis, or whole genome sequencing.

14. The method of claim 11 , wherein the NRF2 pathway antagonist is a CREB antagonist, a CREB Binding Protein (CBP) antagonist, a Maf antagonist, an activating transcription factor 4 (ATF4) antagonist, a protein kinase C (PKC) antagonist, a Jun antagonist, a glucocorticoid receptor antagonist, a UbcM2 antagonist, a HACE1 antagonist, a c-Myc agonist, a SUMO agonist, a KEAP1 agonist, a CUL3 agonist, or a retinoic acid receptor a (RARα) agonist.

15. The method of claim 11 , wherein the sample obtained from the subject is a tumor sample.

16. The method of claim 15 , wherein the tumor sample is from a biopsy.

17. The method of claim 11 , wherein the subject has a lung cancer or a head and neck cancer.

18. The method of claim 17 , wherein the head and neck cancer is a squamous head and neck cancer.

19. The method of claim 17 , wherein the lung cancer is a non-small cell lung cancer (NSCLC).

20. The method of claim 19 , wherein the NSCLC is a squamous NSCLC.

Assignees

• Genentech Inc
• Found Medicine Inc

Inventors

• Klijn Christiaan Nicolaas
• Lee James
• Stokoe David Hugh
• Gentleman Robert
• Gnad Florian
• Goldstein Leonard David
• Chmielecki Juliann
• Hartmaier Ryan J

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q1/686

  Polymerase chain reaction [PCR] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title