PMID- 24613036 OWN - NLM STAT- MEDLINE DCOM- 20140620 LR - 20220317 IS - 1532-1967 (Electronic) IS - 0305-7372 (Linking) VI - 40 IP - 6 DP - 2014 Jul TI - Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. PG - 750-9 LID - S0305-7372(14)00023-1 [pii] LID - 10.1016/j.ctrv.2014.02.003 [doi] AB - The hedgehog (Hh) pathway is aberrantly activated in a number of tumors. In medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, mutations in Hh pathway genes lead to ligand-independent pathway activation. In many other tumor types, ligand-dependent activation of Hh signaling is potentiated through crosstalk with other critical molecular signaling pathways. Among such pathways, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest because agents that selectively inhibit these pathways are available and can be readily combined with agents such as vismodegib, sonidegib (LDE225), and BMS-833923, which target smoothened-a key Hh pathway regulator. Numerous preclinical studies have revealed the ways in which Hh intersects with each of these pathways, and combination therapies have resulted in improved antitumor efficacy and survival in animal models. Hh also plays an important role in hematopoiesis and in the maintenance of BCR-ABL-driven leukemic stem cells. Thus, combined inhibition of the Hh pathway and BCR-ABL has emerged as a promising potential therapeutic strategy in chronic myeloid leukemia (CML). A number of clinical trials evaluating combinations of Hh inhibitors with other targeted agents are now underway in CML and a variety of solid tumors. This review highlights these trials and summarizes preclinical evidence of crosstalk between Hh and four other actionable pathways-RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch-as well as the role of Hh in the maintenance of BCR-ABL-driven leukemic stem cells. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Brechbiel, Jillian AU - Brechbiel J AD - Articulate Science, 300 American Metro Boulevard, Suite 132, Hamilton, NJ 08619, USA. Electronic address: jillian.brechbiel@articulatescience.com. FAU - Miller-Moslin, Karen AU - Miller-Moslin K AD - Articulate Science, 300 American Metro Boulevard, Suite 132, Hamilton, NJ 08619, USA. Electronic address: karen.miller-moslin@articulatescience.com. FAU - Adjei, Alex A AU - Adjei AA AD - Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address: Alex.Adjei@RoswellPark.org. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20140224 PL - Netherlands TA - Cancer Treat Rev JT - Cancer treatment reviews JID - 7502030 RN - 0 (Hedgehog Proteins) RN - 0 (Receptors, Notch) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.2 (Fusion Proteins, bcr-abl) RN - EC 2.7.10.2 (Janus Kinase 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (raf Kinases) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - Animals MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use MH - ErbB Receptors/drug effects/metabolism MH - Fusion Proteins, bcr-abl/drug effects/metabolism MH - Hedgehog Proteins/drug effects/*metabolism MH - Humans MH - Janus Kinase 2/antagonists & inhibitors MH - MAP Kinase Signaling System/drug effects MH - Molecular Targeted Therapy/*methods MH - Neoplasms/*drug therapy/*metabolism MH - Phosphatidylinositol 3-Kinases/drug effects/metabolism MH - Proto-Oncogene Proteins c-akt/drug effects/metabolism MH - Proto-Oncogene Proteins p21(ras)/drug effects/metabolism MH - Receptor Cross-Talk/*drug effects MH - Receptors, Notch/drug effects/metabolism MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/drug effects/metabolism MH - raf Kinases/drug effects/metabolism OTO - NOTNLM OT - Cell signaling OT - Combination chemotherapy OT - Hedgehog OT - Novel antitumor agents OT - Smoothened OT - Targeted therapy EDAT- 2014/03/13 06:00 MHDA- 2014/06/21 06:00 CRDT- 2014/03/12 06:00 PHST- 2013/09/30 00:00 [received] PHST- 2014/02/10 00:00 [revised] PHST- 2014/02/13 00:00 [accepted] PHST- 2014/03/12 06:00 [entrez] PHST- 2014/03/13 06:00 [pubmed] PHST- 2014/06/21 06:00 [medline] AID - S0305-7372(14)00023-1 [pii] AID - 10.1016/j.ctrv.2014.02.003 [doi] PST - ppublish SO - Cancer Treat Rev. 2014 Jul;40(6):750-9. doi: 10.1016/j.ctrv.2014.02.003. Epub 2014 Feb 24.