Head and neck squamous cell carcinoma (HNSCC) is a group of aggressive cancers affecting the head and neck region, including the mouth, throat, voice box, nose, and sinuses (1). While HNSCC rates are decreasing in developed countries, it remains the most common cancer in Southeast Asia, accounting for a staggering 64% of global cases (2). This disproportionate burden highlights a critical public health concern in this region. Traditionally, HNSCC was considered a disease of older adults with a history of tobacco use. Indeed, tobacco remains the primary culprit, particularly in developing countries like India where HNSCC is the leading cancer among men (2, 3). Chronic exposure to carcinogens in tobacco products fuels the development of HNSCC, leading to a high number of genetic mutations within tumors. This complexity, coupled with the presence of multiple potential sites for these cancers in the head and neck region, makes achieving a cure particularly challenging (4). Despite this heterogeneity, researchers are actively searching for targetable genetic mutations, or oncogenes, that could serve as a common thread for treating HNSCC patients across different tumor types. Identifying and targeting these shared vulnerabilities holds promise for improving treatment outcomes for this devastating disease.

A revolutionary approach in cancer treatment is emerging – targeting oncogenic gene fusions. These chimeric genes, formed by the abnormal merging of two separate genes, have become a game-changer, offering a tissue-agnostic strategy for improving patient survival regardless of the tumor's origin (5, 6). Gene fusions arise from structural rearrangements in the DNA, such as translocations, inversions, or deletions. Previously, detecting these abnormalities was challenging. However, with the advent of next-generation sequencing, researchers can now identify multiple fusions, including rare but potentially oncogenic ones, in various solid tumors (7, 8). Interestingly, these fusions often target key players in cancer development, like tyrosine kinases, chromatin regulators, and transcription factors (5). Several fusion events have translated into significant clinical progress. The US Food and Drug Administration has approved several drugs targeting specific fusion proteins, ushering in a new era of tumor-agnostic therapies (9-16). These drugs, like larotrectinib and entrectinib for NTRK fusions, selpercatinib for RET fusions, and dabrafenib/trametinib for BRAF fusions, demonstrate the remarkable impact of targeting gene fusions in solid tumors. By identifying and targeting these unique genetic anomalies, researchers are offering new hope for battling cancer, regardless of its location. This shift towards a tissue-agnostic approach holds immense promise for improving patient outcomes in the fight against this complex disease.

Unlike many other solid tumors, the landscape of gene fusions in HNSCC remains largely unexplored. While scattered reports have identified specific fusions, such as FGFR3-TACC3 and MYB-NFIB, their presence and clinical significance are not fully understood (6, 17). Intriguingly, in vitro studies suggest that FGFR3-TACC3 fusions might play a role in resistance to existing therapies targeting EGFR/ERBB3 in HNSCC (18). These findings hint at the potential of gene fusions as both diagnostic markers and therapeutic targets. Currently, data on gene fusions in HNSCC is limited to a handful of studies on tumor samples, cell lines, and lacks substantial clinical data (19-21). There are no FDA-approved drugs that specifically target fusion genes in head and neck cancer. This gap in knowledge presents a compelling opportunity. By thoroughly profiling the landscape of structural alterations in HNSCC, we can identify novel fusion transcripts with therapeutic relevance. This deeper understanding could pave the way for the development of targeted therapies, offering new hope for HNSCC patients.

In this article published in npj Precision Oncology, we describe a novel and potentially transformative discovery in head and neck cancer – the UBE3C-LRP5 fusion transcript. This unique inter-chromosomal rearrangement has emerged as a recurrent and therapeutically relevant player in this aggressive disease. Using a combination of whole transcriptome sequencing and RT-PCR, we analyzed 151 head and neck cancer tumors and four cell lines. This comprehensive approach led to the identification of the UBE3C-LRP5 fusion in two variant forms: LRP5-UBE3C and UBE3C-LRP5. Notably, the prevalence of these fusions within our patient samples (4% and 2.6% respectively) is significantly higher than the typical range of rare oncogenic fusions found in other solid tumors (less than 1%). This finding suggests a potentially more prominent role for UBE3C-LRP5 in head and neck cancer development. Furthermore, our analysis of data from The Cancer Genome Atlas (TCGA) revealed the presence of UBE3C-LRP5 fusions in 1.2% of HNSCC patient samples. This aligns with the established prevalence of oncogenic fusions in the literature, adding further weight to the potential significance of UBE3C-LRP5. To validate our findings, we employed whole genome sequencing to pinpoint the exact location where the reciprocal translocation between UBE3C and LRP5 genes occurs. This confirmed the genomic basis for the fusion transcript formation. Functional studies conducted both in vitro and in vivo demonstrated that the UBE3C-LRP5 fusion acts as an activating factor. It promotes the proliferation, migration, and invasion of head and neck cancer cells, hallmarks of aggressive tumor behavior. Conversely, depletion of this fusion transcript led to a suppression of these malignant properties, highlighting its potential as a therapeutic target.

The UBE3C-LRP5 fusion activates the Wnt/β-catenin signaling pathway, a well-known driver of cancer cell growth and invasion. This activation leads to the accumulation of β-catenin in the nucleus, where it triggers the expression of genes like MYC, CCND1, TCF4, and LEF1, all playing a role in uncontrolled cell division and migration. Through biochemical and in vivo studies, we discovered that pyrvinium pamoate, an FDA-approved anthelminthic drug, can target β-catenin and effectively inhibit the Wnt/β-catenin signaling pathway. This translated into a significant reduction in the aggressive behavior of cancer cells harboring the UBE3C-LRP5 fusion, both in laboratory experiments and in animal models. Mice with tumors formed from cells overexpressing the fusion protein showed improved survival when treated with pyrvinium pamoate. Furthermore, our research suggests that the dependence of these fusion-expressing cells on the Wnt/β-catenin pathway is critical. When we silenced key components of the pathway, such as CTNNB1 (β-catenin gene) or LEF1, the cells exhibited reduced proliferation, ability to form colonies, and interestingly, a decreased response to pyrvinium pamoate treatment. These findings paint a compelling picture. The UBE3C-LRP5 fusion emerges as a promising target for HNSCC therapy, and pyrvinium pamoate presents itself as a potential drug candidate for patients whose tumors harbor this specific translocation. Overall, our work not only unveils a novel fusion transcript in HNSCC but also sheds light on its role in cancer development. By characterizing the UBE3C-LRP5 fusion and its link to the Wnt/β-catenin pathway, we pave the way for the development of targeted therapies specifically for patients with this fusion-driven HNSCC. This targeted approach holds immense promise for improving treatment outcomes in this aggressive form of cancer.

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