Identifying an “Achilles’ Heel” in Colon Cancer

Over 1 million cases of colon cancer are diagnosed worldwide each year resulting in approximately 600,000 deaths annually. Disease-causing mutations in the KRAS gene are found in over half of these cases.

In the United States, colon cancer patients are routinely genotyped for KRAS gene mutations and those with mutations are excluded from receiving novel “targeted” therapeutic agents due to a lack of clinical benefit. Thus, patients with KRAS gene mutations are faced with very limited therapeutic options and are subsequently given very poor clinical prognoses.

A recent study published in the Feb.17 issue of Cell has sought to tackle this problem head-on. The study’s lead author is BUSM Assistant Professor, Pharmacology and Medicine, Division of Hematology and Medical Oncology, Anurag Singh, PhD working closely with Daniel Haber MD, PhD and Jeff Settleman PhD at the Massachusetts General Hospital Cancer Center. The researchers identified a network of genes that are hyper-activated in KRAS mutant colon cancers. Within this network is a gene called MAP3K7 or TAK1, which they showed plays a very critical role in promoting colon cancer disease progression. Pharmacological inhibition of TAK1 results in strong killing of affected tumor cells, with minimal effects in “normal” non-mutated cells.

“These findings raise the possibility that anti-TAK1 agents could provide the basis for “personalized” medicine in patients with highly aggressive KRAS mutant colon cancers,” said Singh. Efforts are now underway to identify clinically efficacious TAK1 inhibitors.