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Ref Type Journal Article
PMID (22693356)
Authors Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M, Zifcak B, Ma AW, DellaRocca S, Borek M, Zhai HX, Cai X, Voi M
Title Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling.
URL
Abstract Text Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells.We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action.CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells.CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.

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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
CUDC-907 CUDC-907 5 6
Drug Name Trade Name Synonyms Drug Classes Drug Description
CUDC-907 Fimepinostat HDAC Inhibitor 45 PI3K Inhibitor (Pan) 42 CUDC-907 (fimepinostat) is a dual PI3K and HDAC inhibitor, which prevents activation of the PI3K-AKT-mTOR signal transduction pathway, inhibits tumor cell growth, and promotes apoptosis in cancer cells (PMID: 22693356, PMID: 32459381).
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
PIK3CA mutant Advanced Solid Tumor sensitive CUDC-907 Preclinical - Cell line xenograft Actionable In a preclinical study, CUDC-907 inhibited PIK3CA, blocked downstream AKT pathway activation, and induced apoptosis and cell cycle arrest in both PIK3CA wild-type and PIK3CA mutant human cancer cell lines and xenograft models of multiple tumor types (PMID: 22693356). 22693356
PTEN del prostate cancer sensitive Pictilisib + Vorinostat Preclinical Actionable In a preclinical study, GDC-0941 and Zolinza (vorinostat) acted synergistically to inhibit growth of a human prostate cancer cell line harboring a PTEN deletion in culture (PMID: 9661880, PMID: 22693356). 22693356 9661880
PIK3CA mutant hematologic cancer sensitive CUDC-907 Preclinical - Cell line xenograft Actionable In a preclinical study, CUDC-907 inhibited PIK3CA, blocked downstream AKT pathway activation, and induced apoptosis and cell cycle arrest in both PIK3CA wild-type and PIK3CA mutant human cancer cell lines and xenograft models of multiple solid and hematologic cancers (PMID: 22693356). 22693356
PIK3CA mutant breast cancer sensitive CUDC-907 Preclinical Actionable In a preclinical study, CUDC-907 inhibited growth of human breast cancer cell lines harboring PIK3CA mutations in culture (PMID: 22693356). 22693356
PTEN del breast cancer sensitive CUDC-907 Preclinical - Cell culture Actionable In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356). 22693356
PTEN mutant breast cancer sensitive CUDC-907 Preclinical - Cell culture Actionable In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356). 22693356