Discover how this breakthrough therapeutic target could overcome resistance in advanced basal cell carcinoma
Imagine a patient—let's call him David—who has been battling a persistent basal cell carcinoma (BCC) on his face. As the most common form of skin cancer worldwide, with approximately 3.6 million cases diagnosed annually in the United States alone, BCC is typically highly treatable 8 . But David's case is different.
His cancer has advanced, weaving its way into the delicate structures around his eye and becoming what oncologists classify as locally advanced BCC (laBCC) 5 .
BCC cases diagnosed annually in the US
David initially found hope with vismodegib, a targeted therapy that inhibits the Smo protein, a key driver of BCC growth. For a while, the treatment worked. But then, as happens in many advanced cases, his cancer developed resistance 2 7 .
The tumors began growing again, defying the very medicine that had contained them. Until recently, David would have faced dwindling options. But today, thanks to groundbreaking research, scientists have identified a new therapeutic target that could overcome this resistance: atypical protein kinase C iota/lambda (aPKC ι/λ) 1 2 7 .
aPKC ι/λ offers hope for patients with SMO-inhibitor resistant BCC
To understand why aPKC ι/λ is so important, we must first examine the molecular engine that drives basal cell carcinoma: the Hedgehog (Hh) signaling pathway 5 8 .
In normal development, the Hedgehog pathway acts as a precise communication system that regulates cell growth and differentiation. It's especially active during embryonic development, helping shape our tissues and organs. In adults, however, this pathway is largely silenced, its work completed 5 .
The pathway operates like a carefully controlled security system:
The discovery of the Hedgehog pathway's role in BCC led to a revolutionary treatment approach: SMO inhibitors like vismodegib and sonidegib 5 . These drugs effectively block SMO activity, halting the signaling cascade that drives cancer growth.
Objective response rate in clinical trials for laBCC
Standard systemic treatment for advanced BCC
Clinical Implication: This resistance phenomenon created an urgent need for new therapeutic approaches that could target the Hedgehog pathway beyond SMO, particularly downstream elements that might activate GLI1 directly.
In 2013, a team of researchers led by scientists at Stanford University made a crucial breakthrough. Their work, published in the prestigious journal Nature, identified atypical protein kinase C iota/lambda (aPKC ι/λ) as a key regulator of GLI1 activation in basal cell carcinomas 2 7 .
The team first discovered that aPKC ι/λ and its polarity signaling partners co-localize at the centrosome, the cell's central organizing center. There, they form a complex with a scaffolding protein called MIM (missing-in-metastasis), which was already known to potentiate Hedgehog signaling 2 7 .
Using both genetic techniques (silencing the aPKC ι/λ gene) and pharmacological inhibitors, the researchers demonstrated that loss of aPKC ι/λ function effectively blocked Hedgehog signaling and proliferation of BCC cells 2 7 .
Intriguingly, they discovered that the gene encoding aPKC ι/λ (Prkci) is itself a Hedgehog target gene, creating a positive feedback loop with GLI1. This explained why aPKC ι/λ existed at increased levels in BCCs—the overactive Hedgehog pathway was stimulating its own accelerator 2 7 .
The study generated compelling evidence supporting aPKC ι/λ as a critical therapeutic target. The following table summarizes the central findings from this groundbreaking research:
| Experimental Approach | Key Result | Significance |
|---|---|---|
| Genetic silencing of aPKC ι/λ | Blocked HH signaling & BCC proliferation | Demonstrated necessity of aPKC ι/λ for pathway activity |
| Pharmacological inhibition | Suppressed cancer cell growth | Confirmed therapeutic potential |
| Genomic analysis | aPKC ι/λ and SMO control similar genes | Established parallel pathway importance |
| Molecular studies | aPKC ι/λ phosphorylates GLI1 | Identified direct mechanism of action |
| Resistance models | aPKC ι/λ upregulated in SMO-resistant tumors | Explained bypass mechanism |
| Therapeutic targeting | Suppressed growth of resistant BCC lines | Validated clinical application |
Studying aPKC ι/λ and developing targeted therapies requires specialized research tools. The following table outlines key reagents and their applications in this field:
| Reagent/Method | Function/Application | Role in aPKC ι/λ Research |
|---|---|---|
| aPKC ι/λ inhibitors | Selective pharmacological blockade | Test therapeutic potential in BCC models |
| Genetic silencing (siRNA/shRNA) | Target gene knockdown | Establish aPKC ι/λ necessity for HH signaling |
| Immunofluorescence | Protein localization visualization | Detect centrosomal localization of aPKC ι/λ |
| Co-immunoprecipitation | Protein-protein interaction detection | Identify complexes with MIM and polarity proteins |
| GLI-luciferase reporter | HH pathway activity measurement | Quantify aPKC ι/λ effect on GLI-mediated transcription |
| Phospho-specific antibodies | Detection of phosphorylated GLI1 | Monitor aPKC ι/λ enzymatic activity on its substrate |
| BCC cell lines | In vitro cancer models | Screen anti-tumor effects of aPKC ι/λ targeting |
| SMO-inhibitor resistant lines | Resistance model systems | Test efficacy against treatment-resistant cancer |
| Mouse allograft models | In vivo therapeutic testing | Evaluate tumor suppression in living organisms |
The identification of aPKC ι/λ as a key regulator of GLI1 activation and its role in SMO-inhibitor resistance represents a paradigm shift in how we approach advanced basal cell carcinoma 1 2 7 . This discovery provides:
For patients who have exhausted current options
Hope for cancers that develop against SMO inhibitors
Simultaneously target multiple points in the pathway
The journey from basic molecular discovery to clinical application is long and challenging. Yet the compelling evidence linking aPKC ι/λ to treatment-resistant BCC has ignited interest in developing targeted therapies that could offer new hope for patients like David. As research advances, we move closer to a time when advanced basal cell carcinoma, even when resistant to current treatments, may be effectively controlled through precision approaches targeting aPKC ι/λ and other key players in the Hedgehog pathway.
For patients and families facing advanced BCC, ongoing clinical trials continue to evaluate new treatment options. Consultation with a dermatologist or oncologist specializing in skin cancers can provide the most current information on available therapies.