# US 10,501,805 B2 · Methods for determining responsiveness to MEK/ERK inhibitors

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- Number: US 10,501,805 B2
- Document ID: US10501805B2
- Status: Granted
- Kind: B2
- Application number: 15/301,379
- Filed: 2015-04-03
- Published: 2017-04-27
- Granted: 2019-12-10
- Earliest claimed: 2014-04-04
- Assignees: Crown Bioscience, Inc. (Taicang)
- Applicants: Crown Bioscience, Inc. (Taicang)
- Inventors: Sheng Guo; Wubin Qian; Jinying Ning; Jing Zhang; Jixian Li; Zhu Mei
- Web page: https://patentgrep.com/patent/US10501805B2

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- A61P 35/00: Antineoplastic agents
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A method for predicting the responsiveness of a cancer cell to an MEK inhibitor, comprising detecting the presence of at least one mutation in one or more genes selected from the group consisting of ADAM12, COL14A1, TNN, and TP53, in the cancer cell, by contacting a nucleic acid sample derived from the cancer cell with at least one oligonucleotide which allows specific detection of the mutation; wherein presence of mutation in ADAM12, COL14A1, TNN, TP53 and/or any combination thereof is indicative of decreased responsiveness of the cancer cell to the ERK inhibitor.

## Claims

### Claim 1

A method for treating a patient having cancer, comprising:
obtaining a sample derived from the patient;
detecting in the sample that the ADAM12 gene encodes Q650, R240, C440, Q228, H247, M322, T97, P168, and G308 in the ADAM12 protein and does not have a mutation which results in Q650K, R240L, C440Y, Q228E, H247D, M322I, T97fs, P168L, and G308E in the ADAM12 protein; and
administering an MEK inhibitor to the patient.

### Claim 2 (depends on 1)

The method of claim 1, wherein the sample is a cancer cell or tissue derived from the patient.

### Claim 3 (depends on 1)

The method of claim 1, wherein the MEK inhibitor is Trametinib.

### Claim 4 (depends on 1)

The method of claim 1, wherein the detecting step comprises amplifying at least a portion of the ADAM12 gene with an oligonucleotide as primer to generate an amplification product.

### Claim 5 (depends on 1)

The method of claim 1, wherein the detecting step comprises contacting the sample with an oligonucleotide which specifically hybridizes to the mutation of ADAM12 gene to form a complex.

### Claim 6 (depends on 1)

The method of claim 1, wherein the detecting step involves an assay selected from the group consisting of sequencing, polymerase chain reaction (PCR), mass-spectrometric genotyping, HPLC, SSPC and a hybridization-based assay.

### Claim 7 (depends on 1)

The method of claim 1, wherein the detecting step further comprises determining if the patient has a second mutation in one or more genes selected from the group consisting of COL14A1, TNN, and TP53.

### Claim 8 (depends on 7)

The method of claim 7, wherein the mutation in COL14A1 gene results in R178W, L713_splice, Q1272K, L479I, L1295F, E1024K, P1467S, G737R, K1023T, G966C, or S1512fs in COL14A1 protein; wherein the mutation in TNN gene results in V353M, Y296S, A733P, D707Y, D471Y, P1010T, S71L, D457Y, P1155L, R476C, Q872H, Q261L, D798Y, C1237*, D67N or T823S in TNN protein; wherein the mutation in TP53 gene results in Q331R, C135fs, E285K, V274F, Y220C, P250L, R175H, R248Q, R280K, R248L, C176Y, A307_splice, R273L, R158L, A138fs, H193R, A159D, C277F, R248W, Y220C, V274F, R196*, E224_splice, K164*, M246I, A159V, S241F, C242R, S261_splice, or E339* in TP53 protein.

### Claim 9

A method for treating a patient having cancer, comprising:
obtaining a sample derived from the patient;
detecting in the sample that the ADAM12 gene encodes a mutation which results in Q650K, R240L, C440Y, Q228E, H247D, M322I, T97fs, P168L, and G308E in the ADAM12 protein; and
administering a therapeutic agent to the patient, wherein the therapeutic agent is selected from the group consisting of a c-Met inhibitor, an agent targeting PI3K-Akt-mTOR signaling pathway, a chemotherapeutic agent, an anti-metabolite, an anti-hormonal agent, and an angiogenesis inhibitor.

### Claim 10 (depends on 9)

The method of claim 9, wherein the sample is a cancer cell or tissue derived from the patient.

### Claim 11 (depends on 9)

The method of claim 9, wherein the detecting step comprises amplifying at least a portion of the ADAM12 gene with an oligonucleotide as primer to generate an amplification product.

### Claim 12 (depends on 9)

The method of claim 9, wherein the detecting step comprises contacting the sample with an oligonucleotide which specifically hybridizes to the mutation of ADAM12 gene to form a complex.

### Claim 13 (depends on 9)

The method of claim 9, wherein the detecting step involves an assay selected from the group consisting of sequencing, polymerase chain reaction (PCR), mass-spectrometric genotyping, HPLC, SSPC and a hybridization-based assay.

### Claim 14 (depends on 9)

The method of claim 9, wherein the detecting step further comprises determining if the patient has a second mutation in one or more genes selected from the group consisting of COL14A1, TNN, and TP53.

### Claim 15 (depends on 14)

The method of claim 14, wherein the mutation in COL14A1 gene results in R178W, L713_splice, Q1272K, L479I, L1295F, E1024K, P1467S, G737R, K1023T, G966C, or S1512fs in COL14A1 protein; wherein the mutation in TNN gene results in V353M, Y296S, A733P, D707Y, D471Y, P1010T, S71L, D457Y, P1155L, R476C, Q872H, Q261L, D798Y, C1237*, D67N or T823S in TNN protein; wherein the mutation in TP53 gene results in Q331R, C135fs, E285K, V274F, Y220C, P250L, R175H, R248Q, R280K, R248L, C176Y, A307_splice, R273L, R158L, A138fs, H193R, A159D, C277F, R248W, Y220C, V274F, R196*, E224_splice, K164*, M246I, A159V, S241F, C242R, S261_splice, or E339* in TP53 protein.