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Ref Type Journal Article
PMID (26439693)
Authors Lieu CH, Klauck PJ, Henthorn PK, Tentler JJ, Tan AC, Spreafico A, Selby HM, Britt BC, Bagby SM, Arcaroli JJ, Messersmith WA, Pitts TM, Eckhardt SG
Title Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts.
Journal Oncotarget
Vol 6
Issue 33
Date 2015 Oct 27
Abstract Text CRC is a significant cause of cancer mortality, and new therapies are needed for patients with advanced disease. TAK-733 is a highly potent and selective investigational novel MEK allosteric site inhibitor.In a preclinical study of TAK-733, a panel of CRC cell lines were exposed to varying concentrations of the agent for 72 hours followed by a sulforhodamine B assay. Twenty patient-derived colorectal cancer xenografts were then treated with TAK-733 in vivo. Tumor growth inhibition index (TGII) was assessed to evaluate the sensitivity of the CRC explants to TAK-733 while linear regression was utilized to investigate the predictive effects of genotype on the TGII of explants.Fifty-four CRC cell lines were exposed to TAK-733, while 42 cell lines were deemed sensitive across a broad range of mutations. Eighty-two percent of the cell lines within the sensitive subset were BRAF or KRAS/NRAS mutant, whereas 80% of the cell lines within the sensitive subset were PIK3CA WT. Twenty patient-derived human tumor CRC explants were then treated with TAK-733. In total, 15 primary human tumor explants were found to be sensitive to TAK-733 (TGII ≤ 20%), including 9 primary human tumor explants that exhibited tumor regression (TGII > 100%). Explants with a BRAF/KRAS/NRAS mutant and PIK3CA wild-type genotype demonstrated increased sensitivity to TAK-733 with a median TGII of -6%. MEK-response gene signatures also correlated with responsiveness to TAK-733 in KRAS-mutant CRC.The MEK inhibitor TAK-733 demonstrated robust antitumor activity against CRC cell lines and patient-derived tumor explants. While the preclinical activity observed in this study was considerable, single-agent efficacy in the clinic has been limited in CRC, supporting the use of these models in an iterative manner to elucidate resistance mechanisms that can guide rational combination strategies.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
TAK-733 TAK-733 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
TAK-733 TAK733 MEK inhibitor (Pan) 23 MEK1 Inhibitor 22 MEK2 Inhibitor 20 TAK-733 inhibits MEK1 and MEK2, preventing the activation of the RAS/RAF/MEK/ERK pathway, possibly inhibiting growth factor-mediated cell signaling and tumor cell proliferation (PMID: 26439693, PMID: 30396931).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF mut PIK3CA wild-type colorectal cancer predicted - sensitive TAK-733 Preclinical - Pdx & cell culture Actionable In a preclinical study, mutations in BRAF, KRAS, or NRAS were associated with sensitivity to TAK-733 in colorectal cancer cell lines in culture, and patient-derived xenograft models harboring KRAS or BRAF mutations with wild-type PIK3CA demonstrated a trend toward higher tumor growth inhibition following TAK-733 treatment (PMID: 26439693). 26439693
NRAS mut PIK3CA wild-type colorectal cancer predicted - sensitive TAK-733 Preclinical - Cell culture Actionable In a preclinical study, colorectal cancer cell lines harboring mutations in KRAS or NRAS and with wild-type PIK3CA demonstrated a trend toward increased sensitivity to TAK-733 in culture (PMID: 26439693). 26439693