APKC ι/λ: a potential target for the therapy of Hh-dependent and Smo-inhibitor-resistant advanced BCC

Abstract

Basal cell carcinoma (BCC), a skin cancer, is the most common malignancy in white people [1, 2]. Although mortality is low as BCC rarely metastasizes, people suffering from BCC are at high risk of developing other malignancies [3]. Given its low metastatic potential, treatment of BCC focuses on local control, including surgical and non-surgical measures [3, 4]. In the best hands, the 5-year cure rates of excision, curettage and cautery, and cryosurgery are 95% or higher [3]. However, considering multiple postsurgical recurrences or incurable with surgery without significant deformity or loss of function, locally advanced BCC is inoperable, and so is metastatic BCC [5]. Therefore, looking for inhibitors of specific targets for therapy of BCC based on its molecular pathogenesis is of great importance. Although Vismodegib, approved as the first medicine for adults with advanced BCC (locally advanced BCC and metastatic BCC) by US Food and Drug Administration (FDA) in 2012, appears effective in the treatment of BCC, treatment-driven evolution has resulted in the outgrowth of tumor cell variants resistant to the drug [5]. New targets for BCC treatment are necessary [6–9]. Recently, Atwood et al. [9] reported in Nature that aPKC i/l inhibition would be a viable, tumor-selective alternative to Smo inhibitors, Vismodegib, to treat BCC. Thinking about the severe consequence and the high incidence of BCC, scientists have tried their best to investigate the pathogenesis, and enormous progress has been made in its genetic and molecular mechanism. It has been showed that almost all of the BCCs contain genetic mutations in Hedgehog (Hh) signaling pathway, resulting in aberrant pathway activity and uncontrolled proliferation of basal cells [8]. Molecular and genetic studies further clarified that the growth of BCCs requires the high activity of Hh signaling pathway through the transcription factor, glioma-associated oncogene homolog (GLI) [7]. Based on this, people have tried to translate these insights into improving BCC treatment by targeting Hh signaling pathway. Some clinical trials of inhibitors of Hh signaling pathway have indicated that disruption of Hh signal in tumors can result in therapeutic benefit. Among these inhibitors, Vismodegib, an antagonist of Smo, has been shown to associate with tumor responses in patients with advanced BCC [8] and was approved as the first drug for BCC treatment on January 30, 2012 by US FDA. However, advanced tumors can evolve resistance through pathway-dependent genetic mechanisms or through compensatory adaptation [6]. Some tumor variants can bypass Smo inhibitors and still activate Hh signal, resulting in the secondary (acquired) resistance to the drug [5]. Because the growth of tumor variants with resistance to Vismodegib is also Hh activity-dependent, the most downstream transcription factor GLI or direct regulator(s) of GLI could be potential targets. In order to identify new potential target(s) in Hh pathway for BCC, Atwood et al. used miss in metastasis (MIM), which potentiates GLI-dependent activation downstream of Smo [10], as bait in a biased proteomics screen to identify factors involved in Hh signaling and ciliogenesis. Two of the hits were polarity proteins which were not previously linked to the Hh pathway: aPKC-i/l, a serine/threonine kinase, and PARD3, a aPKC-i/l substrate [9]. The subsequent experiments mainly employed BCC cells as a niche to mimic BCC physiological status. First of all, they performed co-immunoprecipitation assay followed by western blot with anti-MIM antibody or anti-aPKC-i/l antibody to confirm the interaction between MIM and aPKC-i/l in BCC cells. Then, they found that the knocking down of MIM or aPKC-i/l with short hairpin RNA leads to the downregulation of messenger RNA (mRNA) level of Gli1, which is the direct target gene of Hh signaling pathway. In addition, the inhibition of aPKC-i/l kinase activity with myristoylated aPKC peptide inhibitor (PSI) [11] resulted in the decrease of Gli1 mRNA level in a dose-dependent manner, and the growth of the BCC cell was also inhibited at the same condition according to the MTT assay, which has been used widely to measure the cell growth rate. Then, they showed that PSI specifically inhibited aPKC based on the finding Acta Biochim Biophys Sin 2013, 45: 610–611 |a The Author 2013. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmt053. Advance Access Publication 17 May 2013