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AssigneeMemorial Sloan Kettering Cancer Center
InventorsGrazia Ambrosini, Raya Khanin, Richard Carvajal, Gary K. Schwartz
Estimating the term…
The present invention relates to methods and compositions for determining the likelihood that a subject suffering from a cancer will benefit from treatment with a MEK inhibitor. It also relates to methods of treatment based on such determination. The invention is based, at least in part, on the discoveries that DDX43 mRNA and protein are expressed at high levels in biopsies from “non-responder” UM patients and that selumetinib-resistant cell lines showed high DDX43 expression which correlated with increased expression and activity of RAS. It was found that KRAS and HRAS but not NRAS, mediated expression of pERK and pAKT, bypassing oncogenic GNAQ. The invention is further based on the discovery that selumetinib-resistant cells became sensitive to AKT inhibition, suggesting alternative strategies for the treatment of cancer patients with acquired resistance to MEK inhibitors.
A method of determining whether an anti-cancer effect is unlikely to be produced in a cancer by a MEK inhibitor, comprising determining whether cells of the cancer contain an increased level of DDX43 mRNA and/or DDX43 protein, where if the level of DDX43 mRNA and/or protein is increased, it is unlikely that a MEK inhibitor would have an anti-cancer effect on the cancer.
A method of determining whether an anti-cancer effect is unlikely to be produced in a cancer by a MEK inhibitor, comprising determining whether cells of the cancer contain an increased level of mRNA and/or protein corresponding to one or more gene or exon listed in Table 1, where if the level of mRNA and/or protein is increased, it is unlikely that a MEK inhibitor would have an anti-cancer effect on the cancer.
A method of determining whether an anti-cancer effect is unlikely to be produced in a cancer by a MEK inhibitor, comprising determining whether cells of the cancer contain a decreased level of mRNA and/or protein corresponding to an exon of one or more of the following:
A method of treating a subject having a cancer comprising (i) determining whether an anti-cancer effect is unlikely to be produced in the cancer by a MEK inhibitor, comprising determining whether cells of the cancer contain an increased level of DDX43 mRNA and/or DDX43 protein relative to a normal value or normal values;
A method of treating a subject having a cancer comprising (i) determining whether an anti-cancer effect is unlikely to be produced in the cancer by a MEK inhibitor, comprising determining whether cells of the cancer contain an increased level, relative to a normal value or values, of DDX43 mRNA and/or DDX43 protein and/or an increased level, relative to a normal value or values, of mRNA or protein corresponding to one or more gene or exon listed in Table 1, and (ii) treating the subject with a therapeutic amount of a MEK inhibitor if the level of DDX43 mRNA and/or protein, and/or the level of mRNA or protein corresponding to one or more gene or exon listed in Table 1, is not increased or (iii) treating the subject with a therapeutic amount of an anticancer agent other than a MEK inhibitor where the level of DDX43 mRNA and/or protein, and/or the level of mRNA or protein corresponding to one or more gene or exon listed in Table 1, is increased.
A method of treating a subject having a cancer comprising (i) determining whether an anti-cancer effect is unlikely to be produced in the cancer by a MEK inhibitor, comprising determining whether cells of the cancer contain an increased level, relative to a normal value or values, of DDX43 mRNA and/or DDX43 protein and/or a decreased level, relative to a normal value or values, of mRNA or protein corresponding to an exon of one or more of the following:
A kit for determining whether an anti-cancer effect is unlikely to be produced in a cancer by a MEK inhibitor, comprising a means for determining the level of DDX43 mRNA and/or protein in a cell or cells of the cancer together with a disclosure that an increased level of DDX43 expression in a cancer relative to a normal value is associated with a lower likelihood that a MEK inhibitor will have an anticancer effect against the cancer.
A kit for determining whether an anti-cancer effect is likely to be produced in a cancer by a MEK inhibitor, comprising a means for determining the level of mRNA and/or protein, corresponding to DDX43 and/or one or more gene or exon listed in Table 1, in a cell or cells of the cancer.
A kit for determining whether an anti-cancer effect is likely to be produced in a cancer by a MEK inhibitor, comprising a means for determining the level of mRNA and/or protein, corresponding to DDX43 and/or an exon of one or more of the following:
A means for determining the level of DDX43 mRNA or protein, for use in a method of determining whether an anti-cancer effect is unlikely to be produced in a cancer by a MEK inhibitor, said method characterized by determining whether cells of the cancer contain an increased level of DDX43 mRNA and/or DDX43 protein relative to a normal value or values, where if the level of DDX43 mRNA and/or protein is increased, it is unlikely that a MEK inhibitor would have an anti-cancer effect on the cancer.
A MEK inhibitor, for use in treating a cancer in a subject, where it has been determined in the cancer that the level of DDX43 mRNA or protein is not increased relative to a normal value.
Dependencies are inferred from the claim text.