Colorectal Tumors Are Effectively Eradicated by Combined Inhibition of β-Catenin, KRAS, and the Oncogenic Transcription Factor ITF2

Abstract

Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities, including aberrant activation of β-catenin (β-cat) and KRAS, but independent targeting of these molecules seems to have limited therapeutic effect. In this study, we report therapeutic effects of combined targeting of different oncogenes in CRC. Inducible short hairpin RNA (shRNA)-mediated silencing of β-cat, ITF2, or KRAS decreased proliferation by 88%, 72%, and 45%, respectively, with no significant apoptosis in any case. In contrast, combined blockade of β-cat and ITF2 inhibited proliferation by 99% with massive apoptosis. Similar effects occurred after combined shRNA against β-cat and KRAS. In vivo, single oncogene blockade inhibited the growth of established tumors by up to 30%, whereas dual β-cat and ITF2 targeting caused 93% inhibition. Similar tumor growth suppression was achieved by double β-cat/KRAS shRNA in vivo. Our findings illustrate an effective therapeutic principle in CRC based on a combination targeting strategy that includes the ITF2 oncogene, which represents a novel therapeutic target.

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

“…To express p38␥ in HCT116 cells, the retroviral vector pLHCX and pLHCX-p38␥ were used (18). Tet-inducible expression of MKK6-p38␥ fusion protein in MCF-7 cells was described recently (33), whereas Tet-On shRNA against the mutated K-Ras was performed as reported previously (34).…”

“…To examine whether the mutated K-Ras directly controls the p38␥/PTPH1 axis, we used a Tet-On system to deliver the specific shRNAs to deplete the mutated (MT) but not wild-type (WT) K-Ras (34). Results in Fig.…”

Molecular Screening for T315I and F317L Resistance Mutations in Iraqi Chronic Myeloid Leukemia Non-Responders Patients to Imatinib

“…It is likely that the T315V mutation (GTT codon) evolved from the previously identified T315A clone (GCT codon) as a consequence of a second mutational event occurred in the same codon (Redaelli et al, 2012). The targeting of more than a single pathogenic event in a highly heterogeneous cancer could produce better results (Mologni et al, 2010).…”

The Genomics of Lung Adenocarcinoma: Opportunities for Targeted Therapies

“…The observed mutation profile mirrors the previously described pattern of mutations in endometrial carcinoma rather than colorectal carcinomas, also characterized by a high frequency of microsatellite instability; the reasons for this remain unclear. 94 Exploratory preclinical experiments inhibiting β-catenin signaling in colorectal carcinoma with RNA interference against CTNNB1, KRAS, and transcription factor ITF2 or small molecules that stabilize the APC-AXIN-GSK3β destruction complex look promising, 97,98 but these approaches may not easily M Monographs translate to lung adenocarcinoma therapies for patients harboring stabilizing mutations of CTNNB1. Thus, no real progress has been made in targeting oncogenic mutant forms of CTNNB1 in lung cancer.…”

“…92 Because APC and KRAS mutations frequently co-occur in lung adenocarcinoma, the aforementioned therapeutic approach involving simultaneous inactivation of KRAS, CTNNB1, and ITF2 may be applicable to lung adenocarcinoma patients harboring inactivating mutations of APC. 97 Small molecules that stabilize the APC-AXIN-GSK3β destruction complex or destabilize interaction of β-catenin with TCF/LEF transcription factor family members may likewise constitute a reasonable therapeutic approach for such lung adenocarcinoma patients. 98,152 Because of the well-characterized frequency of inactivating APC mutations in colorectal carcinoma, these approaches are primarily being explored in the context of colon cancer; it remains to be seen whether any evidence will be produced supporting these approaches in lung adenocarcinoma cells harboring mutations of APC.…”