TY - JOUR
T1 - An inhibitor of the pleckstrin homology domain of CNK1 selectively blocks the growth of mutant KRAS cells and tumors
AU - Indarte, Martin
AU - Puentes, Roisin
AU - Maruggi, Marco
AU - Ihle, Nathan T.
AU - Grandjean, Geoffrey
AU - Scott, Michael
AU - Ahmed, Zamal
AU - Meuillet, Emmanuelle J.
AU - Zang, Shuxing
AU - Lemos, Robert
AU - Du-Cuny, Lei
AU - Layng, Fabiana I.A.L.
AU - Correa, Ricardo G.
AU - Bankston, Laurie A.
AU - Liddington, Robert C.
AU - Kirkpatrick, Lynn
AU - Powis, Garth
N1 - Funding Information:
Supported by NIH grants CA185054, CA201707 (to G. Powis), and CCSG grant P30CA030199. The help of SBP Cancer Center Animal and Genomic Services is gratefully acknowledged.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/6/15
Y1 - 2019/6/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-18-2372
DO - 10.1158/0008-5472.CAN-18-2372
M3 - Article
C2 - 31040156
AN - SCOPUS:85067333240
SN - 0008-5472
VL - 79
SP - 3100
EP - 3111
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -