An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors.

Autor:	Indarte M; PHusis Therapeutics, La Jolla, California., Puentes R; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Maruggi M; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Ihle NT; MD Anderson Cancer Center, Houston, Texas., Grandjean G; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Scott M; PHusis Therapeutics, La Jolla, California., Ahmed Z; MD Anderson Cancer Center, Houston, Texas., Meuillet EJ; PHusis Therapeutics, La Jolla, California., Zang S; MD Anderson Cancer Center, Houston, Texas., Lemos R Jr; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Du-Cuny L; MD Anderson Cancer Center, Houston, Texas., Layng FIAL; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Correa RG; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Bankston LA; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Liddington RC; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California., Kirkpatrick L; PHusis Therapeutics, La Jolla, California., Powis G; Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, California. gpowis@sbpdiscovery.org.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 Jun 15; Vol. 79 (12), pp. 3100-3111. Date of Electronic Publication: 2019 Apr 30.
DOI:	10.1158/0008-5472.CAN-18-2372
Abstrakt:	Cnk1 (connector enhancer of kinase suppressor of Ras 1) is a pleckstrin homology (PH) domain-containing scaffold protein that increases the efficiency of Ras signaling pathways, imparting efficiency and specificity to the response of cell proliferation, survival, and migration. Mutated KRAS (mut-KRAS) is the most common proto-oncogenic event, occurring in approximately 25% of human cancers and has no effective treatment. In this study, we show that selective inhibition of Cnk1 blocks growth and Raf/Mek/Erk, Rho and RalA/B signaling in mut-KRAS lung and colon cancer cells with little effect on wild-type (wt)-KRAS cells. Cnk1 inhibition decreased anchorage-independent mut-KRas cell growth more so than growth on plastic, without the partial "addiction" to mut-KRAS seen on plastic. The PH domain of Cnk1 bound with greater affinity to PtdIns(4,5)P2 than PtdIns(3,4,5)P3, and Cnk1 localized to areas of the plasma membranes rich in PtdIns, suggesting a role for the PH domain in the biological activity of Cnk1. Through molecular modeling and structural modification, we identified a compound PHT-7.3 that bound selectively to the PH domain of Cnk1, preventing plasma membrane colocalization with mut-KRas. PHT-7.3 inhibited mut-KRas, but not wild-type KRas cancer cell and tumor growth and signaling. Thus, the PH domain of Cnk1 is a druggable target whose inhibition selectively blocks mutant KRas activation, making Cnk1 an attractive therapeutic target in patients with mut-KRAS-driven cancer. SIGNIFICANCE: These findings identify a therapeutic strategy to selectively block oncogenic KRas activity through the PH domain of Cnk1, which reduces its cell membrane binding, decreasing the efficiency of Ras signaling and tumor growth. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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