Clinical treatment responsiveness in recurrent canine lymphoma correlates with Anaphase Promoting Complex activity ​

The development of drug resistant cancer is a chronic threat to those undergoing cancer treatment. Why cells develop resistance to drugs has been studied extensively, with many molecular mechanisms driving the process now understood, yet it remains a chronic problem with few treatment options. In this study we treated companion canines presenting to the Western College of Veterinary Medicine in Saskatoon with drug resistant lymphoma with adjunct metformin along with their normal chemotherapy. We obtained repeated tumor samples from 4 canines undergoing this therapy and assessed RNA obtained from these samples by microarray. We identified a highly interconnected 201 gene set upregulated in the 4 dogs that was associated with tumor progression. This gene set was enriched in genes involved in mitotic progression and chromosome maintenance. We observed that mRNAs encoding substrates of the Anaphase Promoting Complex (APC) were integral to this gene set. Treatment with metformin lowered both protein and RNA levels of these substrates, while relapse resulted in elevated levels once again. The change in APC substrates clearly reflects disease progression, indicating that APC activity is critical for cellular homeostasis and loss of this activity can result in tumor progression. 15 samples isolated from canine tumors or control regions (skin biopsies); includes pre-treatment, remission and relapse of lymphoma