Overcoming resistance to ERBB pathway inhibitors

A technology of inhibitors and small molecule inhibitors, applied in the direction of antibodies, anti-tumor drugs, antibody medical components, etc., can solve problems such as lack of phosphorylation and AKT phosphorylation

Inactive Publication Date: 2013-12-04
MERRIMACK PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Trastuzumab treatment results in loss of ErbB3 phosphorylation, dissociation between ErbB3 and PI3K, and loss of AKT phosphorylation in these cancers

Method used

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  • Overcoming resistance to ERBB pathway inhibitors
  • Overcoming resistance to ERBB pathway inhibitors
  • Overcoming resistance to ERBB pathway inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Example 1: MM-121 blocks ligand-induced ErbB3 activation

[0121] In this example, the anti-ErbB3 monoclonal antibody MM-121 (Ab#6, as disclosed in U.S. Patent No. 7,846,440) was examined in a series of in vitro experiments for its inhibition of ligand-induced activation of ErbB3 phosphorylation and Ability to transduce signals.

[0122] In vitro signaling studies measured by ELISA

[0123] In the first set of experiments, 3 cancer cell lines (ACHN (renal cell adenocarcinoma, ATCC #CRL-1611 TM ), Du145 (prostate cancer, ATCC #HTB-81 TM ) and OvCAR8 (ovarian adenocarcinoma, ATCC #HTB-161 TM) cell line; obtained from the Developmental Therapeutics Program (Developmental Therapeutics Program) of the National Cancer Institute (National Cancer Institute)) were seeded into 96-well plates and cultured overnight (maintenance medium was supplemented with 10% fetal calf serum , 2mM L-glutamine, and Pen-Strep in RPMI-1640 medium; in a humidity-controlled atmosphere at 5%...

Embodiment 2

[0126] Example 2: MM-121 overcomes resistance to erlotinib in an in vitro model of EGFR-wild-type non-small cell lung cancer

[0127] method

[0128] Nine non-small cell lung cancer (NSCLC) cell lines were obtained from the American Type Culture Collection: A549 (ATCC #CCL-185 TM ), EKVX (NCI vial0502454), NCI-H2170 (ATCC #CRL-5928 TM ), NCI-H2347 (ATCC #CRL-5942 TM ), NCI-H322M (ATCC #CRL-5806 TM ), NCI-H358 (ATCC #CRL-5806 TM ), NCI-H441 (ATCC #HTB-174 TM ), NCI-H661 (ATCC #HTB-183 TM ) and SW-900 (ATCC #HTB-59 TM ). The cell lines carry no mutations in their EGFR gene and represent 3 distinct histological subtypes (see Table X below). Cells carrying Ras mutations are indicated.

[0129] At 5,000 cells / well, cells were seeded in a 96-well 3D-culture system (low-binding NanoCulture plate, ScivaX Corporation), and cultured at 37°C in RPMI-1640 medium supplemented with 10% fetal bovine serum and Pen-Strep. After 48 h (after which time spheroids had f...

Embodiment 3

[0139] Example 3: Inhibition of pAKT production in human ovarian cancer cells in vitro

[0140] Materials and methods:

[0141] The A2780 human ovarian carcinoma cell line was initially established from tumor tissue obtained from untreated patients. The A2780cis cell line is cisplatin resistant (Catalog #93112517, Sigma). It is formed by chronic exposure of the cisplatin-sensitive parental A2780 cell line (cat. no. 93112519, Sigma) to increasing concentrations of cisplatin. A2780cis is cross-resistant to melphalan, doxorubicin and irradiation. To maintain resistance, cisplatin was added to the medium every 2-3 passages after attachment.

[0142]Resistance to cisplatin was demonstrated by treating A2780 and A2780cis cells with serial dilutions of cisplatin (0.01-10 [mu]M) for 72 hours. Cell viability was measured using the Cell Titer Glo Assay (Cat# G7570, Promega) according to the manufacturer's instructions.

[0143] The effect of cisplatin on the AKT pathway was determi...

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Abstract

Provided are methods for overcoming resistance to an ErbB pathway inhibitor, such as an EGFR inhibitor or a HER2 inhibitor. The resistance may be acquired resistance to an EGFR inhibitor, such as acquired resistance to gefitinib. In the methods provided, a subject exhibiting resistance to an ErbB pathway inhibitor is selected and both an ErbB 3 inhibitor and a second ErbB pathway inhibitor are administered to the subject, such as an EGFR inhibitor or a HER2 inhibitor. Also provided are methods for inhibiting the growth of a tumor comprising a T790M EGFR mutation by contacting the tumor with an ErbB3 inhibitor and an EGFR inhibitor. Compositions for overcoming resistance to an ErbB pathway inhibitor, comprising both an ErbB 3 inhibitor and a second ErbB pathway inhibitor, such as an EGFR inhibitor or a HER2 inhibitor, are also provided.

Description

Background technique [0001] Receptor tyrosine kinases of the ERBB family include EGFR (HER1), HER2 (ErbB2), ERBB3 (HER3) and ERBB4 (HER4). It has been demonstrated over the past decade that many epithelial cancers require EGFR or HER2 signaling for their growth and survival. Agents targeting EGFR have been used extensively to treat cancers such as lung, colorectal, head and neck, and often in combination with gemcitabine, pancreatic cancer. For example, small molecule tyrosine kinase inhibitors (TKIs) that down-regulate the EGFR signaling pathway have been developed, such as gefitinib (Iressa ) (which is indicated for the treatment of non-small cell lung cancer), Erlotinib (Tarceva ) (which is indicated for the treatment of non-small cell lung cancer and pancreatic cancer) and lapatinib (Tykerb ) (which is indicated for the treatment of HER2-positive breast cancer). In addition, antibodies specific for EGFR have been developed, such as the humanized monoclonal antibody ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/00A61K33/00C07K16/32A61K33/243
CPCC07K2317/31A61K31/337C07K16/2863A61K2039/55A61K45/06A61K39/39558A61K31/513C07K16/32A61K31/7068A61K2039/507A61K2039/505A61K33/24C07K2317/76C07K2317/73A61K31/517A61K31/138A61P35/00A61P43/00A61K33/243A61K2300/00A61K39/395
Inventor G·加西亚W·库巴塞科M·J·拉登兰塔G·麦克贝思C·麦克多纳V·莫尤M·D·翁萨姆M·塞维卡M·温斯泽尔鲍姆张博B·舍贝尔
Owner MERRIMACK PHARMACEUTICALS INC
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