Genetic variations associated with drug resistance

A resistance and anti-mitotic agent technology, applied in the field of genetic variation, can solve problems such as increased resistance to Paclitaxel

Inactive Publication Date: 2011-04-20
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Paclitaxel has not previously been shown to be a substrate of ABCC3, and studies of ectopic ABCC3 overexpression in MDCK or NIH-3T3 cells have indeed failed to demonstrate increased resistance to paclitaxel (41, 42)

Method used

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  • Genetic variations associated with drug resistance
  • Genetic variations associated with drug resistance
  • Genetic variations associated with drug resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0162] Example 1 - Techniques and Assays

[0163] Cell Lines and Viability Assays

[0164] Breast cancer cell lines AU565, BT-474, BT-549, CAMA-1, DU4475, HCC1143, HCC1419, HCC1428, HCC2218, HCC70, Hs578T, KPL-1, MCF-7, MDA-MB-231, MDA-MB- 435S, MDA-MB-436, MDA-MB-453, MDA-MB-468, T-47D, UACC-812, ZR-75-1 and ZR-75-30 were obtained from the American Type Culture Collection (American Type Culture Collection, ATCC, Manassas, VA). Cell lines CAL-120, CAL-148, CAL-51, CAL-85-1, EFM-19, EFM-192A, EVSA-T, and MT-3 were obtained from the German Collection of Microorganisms and Cell Cultures (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, DSMZ, Braunschweig, Germany). All cell lines were maintained in DMEM or RPMI 1640 supplemented with 10% fetal bovine serum (Sigma, St. Louis, MO), non-essential amino acids, and 2 mmol / L L-glutamine. Although annotated as mammary, MDA-MB-435S may actually be of melanoma origin and MT-3 may actually be of colorectal origin based on m...

Embodiment 2

[0187] Example 2 - Molecular Characterization of Cell Lines

[0188] Affymetrix gene expression profiling was performed on cDNA prepared from total mRNA and Affymetrix 100K SNP array profiling was performed on DNA from 44 breast cancer cell lines. Cell lines were classified into luminal and basal-like subtypes based on gene expression using an unsupervised analysis of the 11,000 most differentially expressed genes between cell line groups ( Figure 11 ). Cell lines classified as luminal expressed high levels of estrogen receptor alpha (ER) and many target genes regulated by ER, including GATA3, HNF3A, IGF1R, and XBP1. Cell lines classified as basal express high levels of some or all of the well-documented basal markers vimentin, caveolin, MFGE8 and basal cytokines such as KRT5 (31). Because amplification of the HER2 oncogene clearly defined a discrete disease subtype that was not clearly grouped according to overall gene expression in the cell lines (14), HER2 copies were de...

Embodiment 3

[0189] Example 3 - Sensitivity to anti-mitotic drugs in vitro

[0190] Thirty-one breast cancer cell lines were screened for sensitivity to paclitaxel and MMAE in vitro. Figure 11 IC50 values ​​are shown for each compound in all cell lines, defined as the concentration required for 50% inhibition of cell viability in a standard luciferin-based viability assay. Notably, there was a significant correlation between the relative sensitivity to each agent between the cell line groups (Spearman rank-order correlation coefficient, rs=0.55). In addition, Figure 1 shows that compared with luminal or HER2-amplified cell lines, cells with basal-like gene Cell lines expressing the signature had lower mean IC50 values ​​and were more sensitive to each agent.

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Abstract

Methods and compositions are provided to determine if a cancer is resistant to treatment with anti-mitotic agents, including treatment with T-DM1. The methods relate to determining if the ABCC3 gene is amplified and/or overexpressed in the cancer.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 61 / 036,874, filed March 14, 2008, and U.S. Provisional Application Serial No. 61 / 054,064, filed May 16, 2008, both of which are incorporated by reference in their entirety This article. field of invention [0002] In general, the invention relates to genetic variations that are predictive of drug resistance. Background of the invention [0003] A key goal of modern molecular biology is to identify the underlying genetic and genomic variations that characterize a given tumor, allowing patients to receive targeted therapy with chemotherapeutic agents likely to provide the greatest benefit. Breast cancer is the most common form of cancer among women in the Western world, with an estimated 1 million new diagnoses and 400,000 deaths per year worldwide (1). The advent of targeted therapies such as tamoxifen (2) for estrogen receptor-positive cancers and Herceptin (3) for tumors conta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCA61K47/48584C12N15/1138A61K47/48407C12Q2600/106C12N2310/14C12Q1/6886A61K47/6809A61K47/6855A61P15/14A61P35/00A61P43/00G01N33/15
Inventor 马克·拉克纳卢卡斯·C·阿姆勒盖伊·卡维特卡罗尔·奥布赖恩阿杰伊·潘迪塔
Owner GENENTECH INC
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