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