In the ongoing battle against cancer, the quest for more effective treatments has led researchers to explore the intricate workings of cellular responses to therapies.
A team of researchers at the University of Toronto‘s Donnelly Centre for Cellular and Biomolecular Research, led by Dr. Grant Brown — a Professor in the Department of Biochemistry — has discovered two proteins that reduced the efficacy of the certain chemotherapy drugs against pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer. Their findings were published in Nature Cancer.
Gemcitabine, a cornerstone in cancer treatment regimens such as chemotherapy, functions by inducing DNA damage in cancer cells, which leads to their death. Using advanced genetic screening techniques, Brown’s team identified a pair of proteins — APOBEC3C (A3C) and APOBEC3D (A3D) — as key players in modulating the body’s sensitivity to gemcitabine in patients with PDAC.
Conventionally, APOBEC3 proteins are thought to induce mutations and promote tumour evolution and growth. However, in this study, A3C and A3D were found to protect cells from gemcitabine-induced DNA damage, thus promoting cancer cell survival.
The researchers proposed that gemcitabine treatment may actually trigger the production of A3C and A3D. This in turn leads to the recruitment of enzymes that mitigate replication stress — a major cause of genome instability — therefore promoting cell survival.
Importantly, the protective roles of A3C and A3D were specific to cancer cells, highlighting a potential vulnerability that could be exploited for therapeutic purposes. In PDAC cells, the disruption of A3C or A3D led to increased replication stress, which ultimately resulted in decreased cancer cell viability.
Furthermore, the study demonstrated that targeting A3C or A3D enhanced the efficacy of gemcitabine treatment in PDAC cells, providing a promising avenue for combination therapies. Inhibiting these proteins not only reduced tumour growth, but also delayed the emergence of therapy-resistant tumour cells.
This groundbreaking research deepens our understanding of cancer biology and offers new insights into precision medicine. By uncovering the intricate molecular mechanisms underlying gemcitabine resistance, the study paves the way for the development of more effective therapeutic strategies tailored to individual cancer types.
