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Methods of Diagnosing and Treating Cancer in Patients Having or Developing Resistance to a First Cancer Therapy

a cancer therapy and cancer patient technology, applied in the field of cancer patients having or developing resistance to a first cancer therapy, can solve the problems that the clinical response to targeted anticancer therapy is often confused by de novo or acquired resistance, and achieve the effect of effective long-term treatment strategy

Inactive Publication Date: 2013-03-07
THE BROAD INST INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about finding ways to make cancer treatment more effective and identifying which patients would benefit from it. It looks at developing resistance to treatment and finding new targets to help make treatment more effective over the long term.

Problems solved by technology

However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance.

Method used

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  • Methods of Diagnosing and Treating Cancer in Patients Having or Developing Resistance to a First Cancer Therapy
  • Methods of Diagnosing and Treating Cancer in Patients Having or Developing Resistance to a First Cancer Therapy
  • Methods of Diagnosing and Treating Cancer in Patients Having or Developing Resistance to a First Cancer Therapy

Examples

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example 1

An ORF-Based Functional Screen Identifies Specific Kinases as Drivers of Resistance to B-RAF Inhibition

[0104]To identify kinases capable of circumventing RAF inhibition, 597 sequence-validated kinase ORF clones representing ˜75% of annotated kinases (Center for Cancer Systems Biology (CCSB) / Broad Institute Kinase ORF Collection) were assembled and stably expressed in A375, a B-RAFV600E malignant melanoma cell line that is sensitive to the RAF kinase inhibitor PLX4720 (Tsai, J. et al. Proc. Natl. Acad. Sci. USA 105, 3041-3046 (2008)) (FIG. 1a, 1b, Table 3, FIG. 6c). ORF expressing cells treated with 1 μM PLX4720 were screened for viability relative to untreated cells and normalized to an assay-specific positive control, MEK1S218 / 222D (MEK1DD) (Emery, C. M. et al. Proc. Natl. Acad. Sci. USA 106, 20411-20416 (2009).) (Table 4 and summarized in FIG. 5). Nine ORFs conferred resistance at levels exceeding two standard deviations from the mean (FIG. 1b and Table 4) and were selected for fo...

example 2

Resistance to B-RAF Inhibition Via MAPK Pathway Activation

[0106]Whether the overexpression of these genes was sufficient to activate the MAPK pathway was also tested. At baseline, COT expression increased ERK phosphorylation in a manner comparable to MEK1DD, consistent with MAP kinase pathway activation (FIGS. 2a and 10). Overexpression of wild-type COT or C-RAF resulted in constitutive phosphorylation of ERK and MEK in the presence of PLX4720, whereas kinase-dead derivatives had no effect (FIGS. 2a and 11). Thus, COT and C-RAF drive resistance to RAF inhibition predominantly through re-activation of MAPK signaling. Notably, of the nine candidate ORFs from the initial screen, a subset (3) did not show persistent ERK / MEK phosphorylation following RAF inhibition, suggesting MAPK pathway-independent alteration of drug sensitivity (FIG. 12).

example 3

C-RAF Activation and Heterodimerization with B-RAF

[0107]C-RAF activation and heterodimerization with B-RAF constitute critical components of the cellular response to B-RAF inhibition. In A375 cells, endogenous C-RAF: B-RAF heterodimers were measurable and inducible following treatment with PLX4720 (FIG. 13). However, endogenous C-RAF phosphorylation at S338—an event required for C-RAF activation—remained low (FIG. 13). In contrast, ectopically expressed C-RAF was phosphorylated on S338 (FIG. 13) and its PLX4720 resistance phenotype was associated with sustained MEK / ERK activation (FIGS. 2a and 13). Moreover, ectopic expression of a high-activity C-RAF truncation mutant (C-RAF(W22) was more effective than wild-type C-RAF in mediating PLX4720 resistance and ERK activation (FIG. 14), further indicating that elevated C-RAF activity directs resistance to this agent. Consistent with this model, oncogenic alleles of NRAS and KRAS conferred PLX4720 resistance in A375 cells (FIG. 2b) and yie...

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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.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of the filing date under 35 U.S.C. §119(e) of the following Provisional U.S. Patent Application Serial Nos. 61 / 312,193, filed Mar. 9, 2010; 61 / 312,519, filed Mar. 10, 2010; 61 / 326,021, filed Apr. 20, 2010; and 61 / 415,569, filed Nov. 19, 2010, all of which are hereby incorporated by reference in their entirety.FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under federal grant numbers K08 CA115927 and 1DP20D002750 awarded by National Institutes of Health. The government has certain rights in the invention.BACKGROUND[0003]Oncogenic mutations in the serine / threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. (Davies, H. et al., Nature 417, 949-954 (2002).) Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma (Hoeflich, K. P. et...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/437C40B30/04G01N33/574C40B30/06A61K31/4439A61P35/00A61K31/444A61K31/167A61K31/166A61K31/353A61K31/5377A61K31/18C12Q1/68A61K31/44
CPCA61K31/4184C12N9/1205C12Q2600/158C12Q2600/106C12Q1/6886C12N9/12C12Y207/11024A61P35/00A61P35/02A61P43/00G01N33/6893
Inventor GARRAWAY, LEVI A.JOHANNESSEN, CORY M.
Owner THE BROAD INST INC
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