Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	6	33	2015 Oct 27	34561-72	Oncotarget

URL

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	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TAK-733		TAK733\|REC-4881\|REC4881\|REC 4881	MEK inhibitor (Pan) 26 MEK1 Inhibitor 26 MEK2 Inhibitor 24	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
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
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