Researchers developed a mouse model that enabled them to alternately silence and reactivate the tumor suppressor gene adenomatous polyposis coli, which is mutated in the majority of human colorectal cancers. When the tumor suppressor gene was reactivated, the tumors completely regressed within 2 weeks, even in the presence of mutations that commonly sustain disease progression.

Reactivating a tumor suppressor gene that is mutated in the majority of human colorectal cancers led to rapid tumor regression and restoration of normal cell function in mice, according to findings from a recent study that may help spur development of targeted treatments (Cell 2015;161:1539–52).

Researchers used RNAi to generate transgenic mice in which they could alternately silence and restore expression of the tumor suppressor gene adenomatous polyposis coli (APC) by administering or withdrawing doxycycline. As expected, they found that APC suppression produced tumors in the small intestine and colon triggered by deregulation of the Wnt signaling pathway, which controls cell proliferation and survival. Within 2 weeks of APC restoration, the tumors completely regressed, and there were no signs of relapse over a 6-month follow-up period, even in tumors containing p53 or KRAS mutations.

“We've known that the APC gene is important to drive the initial events of colorectal cancer, but not whether it is required to sustain tumor growth,” says the study's senior author Scott Lowe, PhD, chair of the Cancer Biology and Genetics Program at Memorial Sloan Kettering Cancer Center in New York, NY. “Instead of deleting the gene, which is the standard method, we used a genetic trick to silence it and turn it back on, which allowed us to see not only what initiates a cancer but also what maintains it once it's already formed.”

The ability to alternately silence and reactivate APC expression solves a long-standing problem of how to suppress gene expression without completely blocking Wnt signaling and damaging normal intestinal cells, says Lowe. He noted that normal cell differentiation began to occur almost immediately following APC restoration, suggesting that only partial inhibition of Wnt signaling is required to induce tumor regression, thus sparing surrounding normal tissue.

Lowe's team was surprised to observe that suppressing APC expression led to rapid regression in tumors with KRAS and p53 mutations, which are found in about half of all colorectal tumors. While it was known that these mutations promote tumor growth in APC-mutated colorectal cancer, it was not known whether they would continue to drive disease progression when APC is active.

“We thought that KRAS and p53 mutations would at least blunt the ability of APC to regress the tumor,” says Lowe. “Instead it appears that by restoring this one gene in tumors with multiple genetic alterations, the tumor cells go through a normal process of differentiation and some even seem capable of returning to normal stem cells.”

The findings may help inform efforts to develop drugs that target the Wnt pathway, says Lowe. Recently, small-molecule tankyrase inhibitors have shown promise in cell culture and animal studies for modulating Wnt signaling and potentially suppressing colorectal cancers driven by APC mutations.

“This study might be the best validation to date of the Wnt pathway as a therapeutic target,” says Lowe. “What's most exciting is the discovery that, with the right coaxing, it's possible to restore normal functions in a tumor that has multiple genetic changes.”

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2015 American Association for Cancer Research.
2015