Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy
AssigneesDana-Farber Cancer Institute, Inc., The Broad Institute, Inc.
InventorsLevi A. Garraway, Cory M. Johannessen
Life of this patent
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Abstract
A method of identifying a subject having cancer who is likely to benefit from treatment with a combination therapy with a RAF inhibitor and a second inhibitor is provided. A method of treating cancer in a subject in need thereof is also provided and includes administering to the subject an effective amount of a RAF inhibitor and an effective amount of a second inhibitor, wherein the second inhibitor is a MEK inhibitor, a CRAF inhibitor, a CrkL inhibitor or a TPL2/COT inhibitor. A method of identifying a kinase target that confers resistance to a first inhibitor is also provided.
Claims12
A method of identifying and treating a subject having cancer who is likely to benefit from treatment with a combination therapy with a RAF inhibitor and a second inhibitor, comprising:
- assaying a gene copy number, a mRNA or a protein level or phosphorylation of one or more kinase targets selected from the group consisting of MAP3 KB (TPL2/COT), RAF1 (CRAF), CRKL (Crkl), FGR (Fgr), PRKCE (Prkce), PRKCH (Prkch), ERBB2 (ErbB2), AXL (Axl), and PAK3 (Pak3) in cancer cells obtained from the subject and comparing the gene copy number, the mRNA or the protein level or the phosphorylation with a gene copy number, a mRNA or a protein level or phosphorylation of the target kinase in cells obtained from a subject without the cancer;
- identifying the subject having cancer with increased gene copy number or an alteration in mRNA expression or protein overexpression or phosphorylation of the target kinase in the cancer cells relative to the cells from the subject without the cancer as the subject having the cancer who is likely to benefit from treatment with the combination therapy;
- and
- treating the subject having cancer with increased gene copy number or an alteration in mRNA expression or protein overexpression or phosphorylation of the target kinase in the cancer cells with the combination therapy with a RAF inhibitor selected from a group consisting of RAF265, sorafenib, SB590885, PLX 4720, PLX4032, GDC-0879 and ZM 336372 and a second inhibitor selected from the group consisting of a CRAF inhibitor, a Crkl inhibitor and a TPL2/COT inhibitor selected from the group consisting of 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)-3-cyano-[1,7]-naphthyridine, the inhibitory RNA of SEQ ID NO:
- 16, and the inhibitory RNA of SEQ ID NO:
- 17.
A method of identifying and treating a subject having cancer who is likely to benefit from treatment with a combination therapy with a RAF inhibitor and a second inhibitor, comprising:
- assaying a gene copy number, a mRNA or a protein level of MAP3 KB (TPL2/COT) or phosphorylation of C-RAF at amino acid S338 in cancer cells obtained from the subject and comparing the gene copy number, the mRNA or the protein level or the phosphorylation with a gene copy number, a mRNA or a protein level or phosphorylation of the target kinase in cells obtained from a subject without the cancer;
- identifying the subject having cancer with increased gene copy number or an alteration in mRNA expression or protein overexpression or phosphorylation of the target kinase in the cancer cells relative to the cells from the subject without the cancer as the subject having the cancer who is likely to benefit from treatment with the combination therapy;
- and
- treating the subject having increased gene copy number or an alteration in mRNA expression or protein overexpression or phosphorylation of the target kinase in the cancer cells with the combination therapy with a RAF inhibitor selected from a group consisting of RAF265, sorafenib, SB590885, PLX 4720, PLX4032, GDC-0879 and ZM 336372 and a second inhibitor selected from the group consisting of a CRAF inhibitor, a Crkl inhibitor and a TPL2/COT inhibitor selected from the group consisting of 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)-3-cyano-[1,7]-naphthyridine, the inhibitory RNA of SEQ ID NO:
- 16, and the inhibitory RNA of SEQ ID NO:
- 17.
Dependencies are inferred from the claim text.