Treating endometrial, colon cancers by targeting a mutated gene

MD Anderson scientists have discovered mutations in a gene that allow tumors to form and grow.

In this month’s issue of Cancer Cell, Gordon Mills, M.D., Ph.D., and Lydia Cheung, Ph.D., report that mutations on the gene PIK3R1 activate enzymes known as ERK and JNK, which prevent cell death. Tumors form when cells that are genetically programmed to die refuse to do so.

Since its discovery two decades ago, the PIK3R1 gene has been thought to impact the PI3K signaling pathway — a symphony of cell-to-cell communication that triggers a biochemical chain of events, in this case, a tumor.

The PI3K signaling pathway has long been known to play a role in cancer cell proliferation, and targeting why and how PI3K allows tumor cells to grow has been an important area of study and treatment.

“We found that the PIK3R1 mutation, named R348, is a ‘neomorph’ that changes the very nature of the gene itself, and unexpectedly activates the ERK and JNK signaling cascades rather than the normal PI3K pathway. Mutations in close proximity to R348 exhibit the same effects,” said Cheung, the paper’s first author.

“PIK3R1 mutations are particularly prevalent in endometrial and colon cancers,” said Mills, chair of Systems Biology at MD Anderson and the study’s leader.

Standard therapies today center on the cancer gene as a whole, but Mills’ and Cheung’s study suggests that targeted therapies may need to focus on the gene mutation specifically.

“The effective implementation of targeted therapy ultimately lies in the individualization of treatment regimens based on targeting specific mutations,” said Mills. “Our studies show that the cancer gene aberration, rather than the cancer gene alone, will need to be considered for effective therapy.”