Avatars Identify Genetic Sources of Drug Response

Using mouse avatars, researchers have uncovered new mutations in colorectal cancer that enable tumors to resist cetuximab, a standard therapy for the cancer. According to a study published in Nature, the mice also allowed scientists to evaluate treatments that might overcome resistance.

Genome sequencing of tumors can reveal mutations that might lead to drug resistance and may identify determinants of sensitivity. Mouse avatars, rodents implanted with small pieces of human tumors, may enable researchers to test whether cancers with particular mutations will respond to certain drugs.

For patients with late-stage colorectal cancer, standard therapies are cetuximab (Erbitux; Eli Lilly) and panitumumab (Vectibix; Amgen), both of which block EGFR. However, de novo or acquired resistance is common. Although mutations in KRAS and several other genes promote resistance to the EGFR inhibitors, it is likely that additional mechanisms exist.

To search for new mechanisms, Victor Velculescu, MD, PhD, of Johns Hopkins School of Medicine in Baltimore, MD, and colleagues generated mouse avatars from 129 KRAS wild-type liver metastases from late-stage colorectal cancers and performed exome sequencing on tumor and matched normal DNA.

Next, the authors treated the mouse avatars with cetuximab and assessed tumor volume over 6 weeks. Thanks to the avatars, the researchers identified several potential resistance mutations. Previous studies had implicated amplifications of ERBB2, but the team found point mutations that produced resistance. The scientists also pinpointed mutations in the kinase domain of EGFR, amplifications of FGFR1, and alterations in PDGFRA and MAP2K1.

The team next tested whether targeting these mutations could curb tumor growth in the mouse avatars. The combination of cetuximab and the FGFR inhibitor BGJ398, which is in clinical trials for several types of cancer, halted the growth of tumors with FGFR1 amplifications. Similarly, tumors with mutations in the kinase domain of EGFR shrank after treatment with cetuximab and afatinib (Gilotrif; Boehringer Ingelheim), an EGFR tyrosine kinase inhibitor. The researchers also saw positive effects from therapies designed for tumors with mutations in PDGFRA and MAP2K1.

“We now understand at the molecular level the vast majority of mechanisms of resistance to anti-EGFR therapy” in colorectal cancer, says Velculescu.

The scientists also found that mutations in IRS2 may lead to increased sensitivity to anti-EGFR therapy, suggesting a way to identify patients who are most likely to experience long-lasting treatment benefits.

“This is a great example of using avatars to advance the sequencing findings to treatment,” says X. F. Steven Zheng, PhD, of Rutgers University in New Brunswick, NJ, who wasn't involved with the research. “This type of study could be extended to other types of tumors,” he says.

Velculescu says that he and his colleagues aim to launch clinical trials of some of the drug combinations they tested in the mice.