Gene expression markers of tumor resistance to her2 inhibitor treatment

Abstract

The present invention concerns markers of resistance of HER2 expressing tumors to treatment with HER2 inhibitors, such as HER2 antibodies, including trastuzumab.

What is claimed is: 
     
         1 . A method of increasing the likelihood of response of a mammalian subject diagnosed with a HER2 expressing tumor to treatment with a HER2 inhibitor, comprising:
 (a) measuring in a tumor cell sample obtained from said human subject, a lower expression level of the RNA transcript or expression product of a PTPN11 gene relative to the expression level of PTPN11 gene in a normal cell of the same cell type, wherein the identical or increased expression level identifies the subject as not likely to be resistant to treatment with said HER2 inhibitor, and   (b) treating the subject with said HER2 inhibitor.   
     
     
         2 . The method of  claim 1  wherein the mammalian subject is a human patient. 
     
     
         3 . The method of  claim 2  wherein the cancer expresses HER2 at least at a 1+ level. 
     
     
         4 . The method of  claim 2  wherein the cancer expresses HER2 at least at a 2+ level. 
     
     
         5 . The method of  claim 2  wherein the cancer expresses HER at a 3+ level. 
     
     
         6 . The method of  claim 2  wherein the tumor is selected from the group consisting of breast cancer, squamous cell cancer, small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, tumors of the biliary tract, and head and neck cancer. 
     
     
         7 . The method of  claim 2  wherein the tumor is selected from the group consisting of stomach, endometrium, salivary gland, lung, kidney, colon, thyroid, pancreas and bladder, and prostate cancer. 
     
     
         8 . The method of  claim 2  wherein the tumor is breast cancer. 
     
     
         9 . The method of  claim 8  wherein the tumor is metastatic breast cancer. 
     
     
         10 . The method of  claim 2  wherein the HER2 inhibitor is an agent which interferes with HER2 activation or function. 
     
     
         11 . The method of  claim 2  wherein the HER2 inhibitor is a HER2 antibody or an antigen-binding fragment thereof, a small molecule HER2 antagonist, a HER2 tyrosine kinases inhibitor, or an antisense molecule. 
     
     
         12 . The method of  claim 11  wherein the HER2 inhibitor is a HER2 antibody or an antigen-binding fragment thereof, or a small molecule which binds to and inhibits the HER2 receptor. 
     
     
         13 . The method of  claim 12  wherein the HER2 antibody inhibits HER2 ectodomain cleavage. 
     
     
         14 . The method of  claim 12  wherein the HER2 antibody blocks ligand activation of a HER receptor. 
     
     
         15 . The method of  claim 12  wherein the HER2 antibody inhibits HER2 dimerization. 
     
     
         16 . The method of  claim 12  wherein the HER2 antibody or the antigen-binding fragment binds to the heterodimeric binding site of HER2. 
     
     
         17 . The method of  claim 12  wherein the HER2 antibody or antigen-binding fragment binds to the 4D5 epitope. 
     
     
         18 . The method of  claim 17  wherein the HER2 antibody or antigen-binding fragment is selected from the group consisting of humanized antibodies huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and trastuzumab, and fragments thereof. 
     
     
         19 . The method of  claim 18  wherein the HER2 antibody or antibody fragment is trastuzumab or an antigen-binding fragment thereof. 
     
     
         20 . The method of  claim 12  wherein the HER2 antibody or antigen-binding fragment blocks ligand activation of a HER2 receptor more effectively than trastuzumab. 
     
     
         21 . The method of  claim 20  wherein the HER2 antibody or antigen-binding fragment binds the 2C4 epitope. 
     
     
         22 . The method of  claim 21  wherein the HER2 antibody or antigen-binding fragment is pertuzumab or a fragment thereof. 
     
     
         23 . The method of  claim 2  wherein said biological sample is a tumor sample. 
     
     
         24 . The method of  claim 23  wherein the tumor sample is from a fixed, wax-embedded cancer tissue specimen of said patient. 
     
     
         25 . The method of  claim 23  wherein the tumor sample is a core biopsy tissue. 
     
     
         26 . The method of  claim 2  wherein said biological sample is biological fluid. 
     
     
         27 . The method of  claim 26  wherein the biological fluid is selected from the group consisting of blood, urine, saliva, ascites fluid, blood serum and blood plasma. 
     
     
         28 . The method of  claim 1 , wherein determination of the expression level is implemented using an apparatus adapted to determine the expression levels of said transcripts or their expression products. 
     
     
         29 . The method of  claim 28 , wherein said determination of the expression levels is performed by using a software program executed by a suitable processor. 
     
     
         30 . The method of  claim 29 , wherein the program is embodied in software stored on a tangible medium. 
     
     
         31 . The method of  claim 30 , wherein the tangible medium is selected from the group consisting of a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.