Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST).

Abstract

BACKGROUND:

c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance.

METHODS:

RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting.

RESULTS:

Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 µM to IM respectively. GIST48 have an IC50 0.66 µM to IM, 0.91 µM to amuvatinib [AMU] and 0.67 µM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63).

CONCLUSION:

Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.

• Authors: Daruka Mahadevan, Noah Theiss, Carla Morales, Amy E Stejskal, Laurence S Cooke, Min Zhu, Drew Kurtzman, Rachel Swart, Evan Ong, Wenqing Qi
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 4 Pg. 1954-66 (Feb 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25557174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Piperazines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pyrimidines
• Quinazolines
• Afatinib
• Imatinib Mesylate
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-kit
• Proto-Oncogene Proteins c-met
• Receptor Protein-Tyrosine Kinases
• Thiourea
• amuvatinib
• Axl Receptor Tyrosine Kinase
• AXL protein, human

Topics

• Afatinib
• Aged
• Aged, 80 and over
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride (pharmacology)
• Female
• Gastrointestinal Stromal Tumors (drug therapy, genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Imatinib Mesylate (pharmacology)
• Immunoblotting
• Immunohistochemistry
• Male
• Middle Aged
• Molecular Targeted Therapy (methods)
• Piperazines
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-kit (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology)
• Quinazolines (pharmacology)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Thiourea
• Axl Receptor Tyrosine Kinase