Most studies searching for biomarkers of treatment response uncover gene mutations associated with poor outcomes in cancer patients. Now a new study by a team of TFRI-funded researchers at BC Cancer has done the opposite, revealing a gene mutation associated with improved survival in patients with Diffuse Large B-cell Lymphoma (DLBCL).
In a paper published in Nature Medicine (April 2020), the team led by Drs. David Scott and Christian Steidl (BC Cancer) discovered that DLBCL patients who exhibit a loss of the TMEM30A protein, a member of the flippase protein complex, respond more favourably to treatment, shining new light on the mechanisms certain drugs use to attack cancer cells.
“In contrast to most studies that describe gene mutations associated with poor survival, we observed that DLBCL cells with complete loss of TMEM30A actually showed increased uptake of cytotoxic drugs, most notably those that are used to treat DLBCL, such as doxorubicin and vincristine,” said Dr. Shannon Healy, a research associate at BC Cancer Research Centre and the paper’s first author.
According to Dr. Healy, the advantage of discovering a gene mutation linked to favourable treatment outcomes is that it helps uncover previously unknown biological mechanisms that explain why some drugs work well on certain patients. In this case, the team found that the TMEM30A mutation and/or deletion alters the cell membrane of DLBCL cells. This membrane separates the interior of the cells from the outside environment and, by altering it, the team hypothesizes that TMEM30A-loss allows drugs to enter the cancer cells more efficiently, leading to better uptake.
This discovery presents a new model that could be exploited to improve drug transport into cancer cells through the use of new therapeutics, according to Dr. Healy.
“Our discovery may inspire and accelerate advances in understanding how membrane physiology can be manipulated to affect drug transport and response in cancer,” she says. “That’s why we are now initiating a large-scale chemical screen to test for possible ‘flippase blockers’ that may produce a new cancer therapeutic that improves drug transport and patients’ responses to treatment.”
In addition to conducting these chemical screens, the team is also hoping to develop an easy-to-use test that measures TMEM30A loss, which could help advance precision medicine approaches to DLBCL.
TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma
Daisuke Ennishi, Shannon Healy, Ali Bashashati, Saeed Saberi, Christoffer Hother, Anja Mottok, Fong Chun Chan, Lauren Chong, Libin Abraham, Robert Kridel, Merrill Boyle, Barbara Meissner, Tomohiro Aoki, Katsuyoshi Takata, Bruce W. Woolcock, Elena Viganò, Michael Gold, Laurie L. Molday, Robert S. Molday, Adele Telenius, Michael Y. Li, Nicole Wretham, Nancy Dos Santos, Mark Wong, Natasja N. Viller, Robert A. Uger, Gerben Duns, Abigail Baticados, Angel Madero, Brianna N. Bristow, Pedro Farinha, Graham W. Slack, Susana Ben-Neriah, Daniel Lai, Allen W. Zhang, Sohrab Salehi, Hennady P. Shulha, Derek S. Chiu, Sara Mostafavi, Alina S. Gerrie, Da Wei Huang, Christopher Rushton, Diego Villa, Laurie H. Sehn, Kerry J. Savage, Andrew J. Mungall, Andrew P. Weng, Marcel B. Bally, Ryan D. Morin, Gabriela V. Cohen Freue, Louis M. Staudt, Joseph M. Connors, Marco A. Marra, Sohrab P. Shah, Randy D. Gascoyne, David W. Scott, and Christian Steidl
This study was partly funded by the Terry Fox New Frontiers Program Project Grant in Overcoming treatment failure in lymphoid cancers