Laboratory-Clinic Interface
Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer

https://doi.org/10.1016/j.ctrv.2014.02.003Get rights and content

Abstract

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.

Introduction

The hedgehog (Hh) pathway is critical for embryonic development and adult homeostasis, but aberrant activation of the Hh pathway is implicated in tumorigenesis [1]. The Hh pathway is therefore an attractive target for anticancer therapy. A number of agents that inhibit smoothened (SMO), a key regulator of this pathway, have been introduced in the clinic [2]. Tumors with activating mutations in this pathway have shown sensitivity to Hh inhibitors, whereas the activity of Hh inhibitors in other tumors has been minimal [2], [3]. Thus, simultaneously targeting Hh and other signaling pathways may prove to be a more effective method for impeding tumor growth. This review discusses the role of the Hh pathway in cancer (alone and in concert with other pathways), the existing preclinical evidence of synergy between Hh inhibitors and other targeted agents in cancer, and ongoing clinical trials investigating these multitargeted combinations.

Section snippets

The role of Hh signaling in cancer

The Hh pathway plays a key role in proliferation and differentiation during embryogenesis [1] and in the regulation of stem cell renewal and tissue homeostasis in the adult [2], [4], [5]. During canonical Hh signaling, three mammalian Hh ligands—sonic hedgehog (SHH), desert hedgehog, and Indian hedgehog—each with distinct spatial and temporal expression patterns, activate Hh signaling by binding to the trans-membrane receptor patched (PTCH), which resides at the base of the primary cilium [6].

Crosstalk between Hh and other signaling pathways in cancer

Evidence of crosstalk between Hh and other signaling pathways has been reported in many tumor types (Fig. 1, Fig. 2). Here we describe interactions with 4 pathways—RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/AKT/mTOR, epidermal growth factor receptor (EGFR), and Notch—that are targets of agents currently used in the clinic as well as the role of Hh in the maintenance of leukemic stem cells (LSCs). Hh

Hh pathway inhibitors

Although several proteins in the Hh pathway (e.g., Hh, SMO, and GLI) have been identified as potential drug targets for inhibiting aberrant Hh signaling, all of the Hh inhibitors currently in clinical development—including vismodegib (GDC-0449), sonidegib (LDE225), PF-04449913, and BMS-833923—target SMO [2], [82]. These inhibitors have improved potency and pharmacokinetics relative to the naturally occurring SMO antagonist cyclopamine, which increases their clinical utility [2], [82]. In early

Synergistic combinations of SMO inhibitors and other targeted agents

Preclinical studies demonstrating synergic cytotoxicity between SMO inhibitors and inhibitors of EGFR, MEK, PI3K/mTOR, Notch/ɣ-secretase, or BCR-ABL are summarized in Table 1.

Clinical trials of SMO inhibitor combinations

Based on the observed crosstalk between Hh and other signaling pathways, several combinations with SMO inhibitors are being evaluated in clinical trials (Table 2) [112]. Most of these trials are still recruiting and do not have published data; however, several studies testing vismodegib have reported preliminary data.

In a phase 1 trial, patients with metastatic pancreatic cancer or advanced solid tumors were treated with vismodegib and erlotinib (n = 15) or vismodegib, erlotinib, and gemcitabine (

Conclusions

The Hh pathway plays a crucial role in the development and progression of many cancers. Single-agent efficacy of Hh inhibitors, however, is limited to tumors with activating genetic derangements in the Hh pathway, such as BCC and medulloblastoma. Evidence of crosstalk between Hh and other signaling pathways during tumorigenesis has led to numerous preclinical combination studies, which have demonstrated synergistic cytotoxicity of SMO inhibitors in combination with EGFR, MEK, PI3K, mTOR,

Conflict of interest statement

J. Brechbiel and K. Miller-Moslin are employees of Articulate Science, a company which received funding from Novartis Pharmaceuticals Corporation to provide medical editorial assistance. A. Adjei has no conflicts to report.

Acknowledgments

The authors thank Karen Kaluza, PhD, (Articulate Science) for medical editorial assistance. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.

References (116)

  • Y. Wang et al.

    The crosstalk of mTOR/S6K1 and hedgehog pathways

    Cancer Cell

    (2012)
  • S. Das et al.

    Nonclassical activation of hedgehog signaling enhances multidrug resistance and makes cancer cells refractory to smoothened-targeting hedgehog inhibition

    J Biol Chem

    (2013)
  • S.Z. Kaylani et al.

    Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Biochem Biophys Res Commun

    (2013)
  • W.K. Wu et al.

    Dysregulation and crosstalk of cellular signaling pathways in colon carcinogenesis

    Crit Rev Oncol Hematol

    (2013)
  • R.L. Bigelow et al.

    Sonic hedgehog induces epidermal growth factor dependent matrix infiltration in HaCaT keratinocytes

    J Invest Dermatol

    (2005)
  • S. Guo et al.

    Role of Notch and its oncogenic signaling crosstalk in breast cancer

    Biochim Biophys Acta

    (2011)
  • J. Domingo-Domenech et al.

    Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells

    Cancer Cell

    (2012)
  • C.Y. Ok et al.

    Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms

    Am J Pathol

    (2012)
  • M.T. Mueller et al.

    Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer

    Gastroenterology

    (2009)
  • T.L. Lin et al.

    Hedgehog pathway as a drug target: smoothened inhibitors in development

    Onco Targets Ther

    (2012)
  • S. Sahebjam et al.

    The utility of hedgehog signaling pathway inhibition for cancer

    Oncologist

    (2012)
  • M. Varjosalo et al.

    Hedgehog: functions and mechanisms

    Genes Dev

    (2008)
  • I. Caro et al.

    The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment

    Clin Cancer Res

    (2010)
  • J. Romer et al.

    Targeting medulloblastoma: small-molecule inhibitors of the sonic hedgehog pathway as potential cancer therapeutics

    Cancer Res

    (2005)
  • B. Belyea et al.

    Embryonic signaling pathways and rhabdomyosarcoma: contributions to cancer development and opportunities for therapeutic targeting

    Sarcoma

    (2012)
  • B. Long et al.

    Activation of the hedgehog pathway in chronic myelogeneous leukemia patients

    J Exp Clin Cancer Res

    (2011)
  • J.W. Theunissen et al.

    Paracrine hedgehog signaling in cancer

    Cancer Res

    (2009)
  • O.J. Becher et al.

    Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas

    Cancer Res

    (2008)
  • C. Dierks et al.

    Essential role of stromally induced hedgehog signaling in B-cell malignancies

    Nat Med

    (2007)
  • G.V. Hegde et al.

    Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target

    Mol Cancer Res

    (2008)
  • S.E. Wilkinson et al.

    Hedgehog signaling is active in human prostate cancer stroma and regulates proliferation and differentiation of adjacent epithelium

    Prostate

    (2013)
  • S.A. O’Toole et al.

    Hedgehog overexpression is associated with stromal interactions and predicts for poor outcome in breast cancer

    Cancer Res

    (2011)
  • R.L. Yauch et al.

    A paracrine requirement for hedgehog signalling in cancer

    Nature

    (2008)
  • H. Tian et al.

    Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis

    Proc Natl Acad Sci USA

    (2009)
  • D. Amakye et al.

    Unraveling the therapeutic potential of the hedgehog pathway in cancer

    Nat Med

    (2013)
  • E. Heller et al.

    Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment

    Cancer Res

    (2012)
  • A.A. Merchant et al.

    Targeting hedgehog–a cancer stem cell pathway

    Clin Cancer Res

    (2010)
  • S. Liu et al.

    Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells

    Cancer Res

    (2006)
  • E.E. Bar et al.

    Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma

    Stem Cells

    (2007)
  • F. Varnat et al.

    Human colon cancer epithelial cells harbour active HEDGEHOG–GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion

    EMBO Mol Med

    (2009)
  • G. Feldmann et al.

    An orally bioavailable small-molecule inhibitor of hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer

    Mol Cancer Ther

    (2008)
  • K.S. Jeng et al.

    Activation of the sonic hedgehog signaling pathway occurs in the CD133 positive cells of mouse liver cancer Hepa 1–6 cells

    Onco Targets Ther

    (2013)
  • C. Zhao et al.

    Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia

    Nature

    (2009)
  • Z. Jagani et al.

    Hedgehog pathway activation in chronic myeloid leukemia

    Cell Cycle

    (2010)
  • C.D. Peacock et al.

    Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma

    Proc Natl Acad Sci USA

    (2007)
  • J. Fu et al.

    NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200

    Neuro Oncol

    (2013)
  • R. Nanta et al.

    NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128

    Oncogenesis

    (2013)
  • A.A. Farooqi et al.

    Wnt and SHH in prostate cancer: trouble mongers occupy the TRAIL towards apoptosis

    Cell Prolif

    (2011)
  • J.H. Kim et al.

    Contrasting activity of hedgehog and Wnt pathways according to gastric cancer cell differentiation: relevance of crosstalk mechanisms

    Cancer Sci

    (2010)
  • M. Chen et al.

    Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

    Mol Cancer

    (2010)
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