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Cassius Marcellus Coolidge's Dogs Playing Poker may have had you fooled – but really, dogs don't smoke cigars, cigarettes or pipes. However, like humans that do not smoke, our canine friends can suffer from lung cancer. In the U.S. alone, nearly 40,000 dogs annually develop canine pulmonary adenocarcinoma, or cPAC. This is an extremely aggressive disease for which there is currently no standard-of-care treatment.



Whilst naturally occurring primary canine lung cancers share clinicopathologic features with human lung cancers, the genetic underpinnings of the disease have remained thus far elusive.



The HER2 gene



That is, until now. One in every five women that develop breast cancer carry a mutation in a gene known as human epidermal growth factor receptor 2 (or, HER2). The HER family of receptors are regulators of cell growth, survival and differentiation, achieved via their activation of multiple signal transduction pathways.



A "ground-breaking" new study led by the Translational Genomics Research Institute (TGen) suggests that the same gene is the cause of lung cancer in many dogs. Their findings, published in the journal Clinical Cancer Research, offer novel avenues for precision medicine in dogs.



Chartering the genomic landscape of canine lung cancer



The study sample included only pet dogs that had naturally occurring cancer, and no dogs were harmed. The scientists performed a multi-platform genomic sequencing analysis of 88 primary canine lung tumors or cell lines. In the cell lines, they then performed functional characterization of HER2 signaling and evaluated the response of the cells to HER2 inhibition by pharmaceutical agents of varying doses.



"These results are the first example of our efforts to adapt genomics tools from the human world, such as gene sequencing and liquid biopsies, to generate novel insights in canine cancers, with mutual benefit for both," said Muhammed Murtaza, Assistant Professor and Co-Director of TGen's Center for Noninvasive Diagnostics, and one of the study's contributing authors.



The sequencing analysis revealed HER2 point mutations in 38% of cPACs, but none in other forms of cancer such as adenosquamous (cPASC) or squamous cell carcinomas.



Ninety three percent of the HER2 mutations found were hotspot V659E transmembrane domain mutations (TMD). Previous structural studies have shown that TMD-mutant HER2 possessed extra hydrogen bonds and/ or salt bridges in the N-terminal dimerization. It is suggested that the effect of this is a preferential adoption of the proteins active state, resulting in increased downstream signaling.1 In human lung cancer, mutations in the TDM are quite rare. In addition to the V659E TMD mutation, the scientists discovered other HER2 mutations in the extracellular domain.



"We found a novel HER2 mutation in nearly half of dogs with cPAC. We now have a candidate therapeutic opportunity for a large proportion of dogs with lung cancer," said Will Hendricks, Assistant Professor in TGen's Integrated Cancer Genomics Division, Director of Institutional Research Initiatives, and the study's senior author.



The first precision medicine clinical trial for dogs with lung cancer



The scientists decided to test the dose response of two HER2 inhibitor drugs, lapatinib and neratinib in cell lines. They found that HER2V659E cPAC cell lines demonstrated significantly higher sensitivity to the HER2 inhibitors when compared to HER2 wild-type cell lines.2



Neratinib is a drug that has been successfully used to treat human breast cancer. Based on the results of this study, a clinical trial is now planned in which neratinib will be used in dogs that have naturally occurring lung cancer with the HER2 mutation.



"This study is ground-breaking because it not only identified a recurring mutation in a canine cancer that had never been found before, but it actually led directly to a clinical trial," said Jeffrey Trent, TGen President and Research Director, and one of the study's contributing authors. "This clinical translation from dog to human and back is the holy grail of comparative cancer research."



"This is the first precision medicine clinical trial for dogs with lung cancer. That is, the selection of cancer therapy for a particular patient is based on the genomic profile of the patient's tumor and matched with agents that are known to specially target the identified mutation," said Wendy Lorch, Associate Professor in the Department of Veterinary Clinical Sciences at The Ohio State University College of Veterinary Medicine, who also will run the study's clinical trial.



Veterinary science benefits from the "genomic era"



Recent advances in sequencing technology have propelled cancer research into a "genomic era" in which precision therapies are in development for certain types of cancer. Now, thanks to the effort of the TGen-Ohio State researchers, veterinary science can hope to experience the same benefits. The next steps of the research will be boosted by a $300,000 grant investment from the Petco Foundation. Susanne Kogut, President of The Petco Foundation, said her organization's investment in the next phase of TGen-Ohio State studies is part of a larger effort to improve the health and welfare of pets everywhere.



References:



1. Ignatius et al. 2017. HER2 Transmembrane Domain (TMD) Mutations (V659/G660) That Stabilize Homo- and Heterodimerization Are Rare Oncogenic Drivers in Lung Adenocarcinoma That Respond to Afatinib. Journal of Thoracic Oncology. DOI:https://doi.org/10.1016/j.jtho.2016.11.2224



2. Lorch et al. 2019. Identification of recurrent activating HER2 mutations in primary canine pulmonary adenocarcinoma. Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-19-1145.