A discovery by scientists at Dana-Farber Cancer Institute and University of Texas Southwestern Medical Center presents drug developers with an entirely new tack in targeting one of the most-wanted molecular culprits in cancer.
The target is a mutant form of the protein KRAS, which has so far proved "undruggable" despite being one of the most commonly altered proteins in human cancers. The researchers found that KRAS's basic structure as a "dimer" — a composite of two similar
or identical proteins — is intrinsic to its ability to function. In either its normal or mutant form, KRAS can't work if it is not a dimer.
The discovery, reported online today in the journal Cell, raises the possibility that drugs that prevent mutant KRAS from forming a dimer could hamper the protein's ability to drive cancer growth.
"The KRAS gene is one of the most frequently mutated genes in human cancers," says Dana-Farber's Pasi A. Jänne, MD, PhD, senior author of the new study with co-senior author Kenneth D. Westover, MD, PhD,
of University of Texas Southwestern Medical Center. "It's mutated in 20-25 percent of lung cancers, making it the largest genomic subtype of lung cancer, as well as in a large percentage of colon,
pancreatic, and other cancers. That kind of prevalence has made the KRAS protein one of the prime targets for new therapies. So far, however, it has resisted targeting with small-molecule drugs."
Although drugs capable of blocking dimerization (the process of forming protein dimers) do not currently exist for cancer or any other disease, the discovery reported by Jänne and his colleagues may prompt new research in this area, the study authors
Like all genes in human cells, the KRAS gene exists in two copies, one inherited from each parent. When one copy of KRAS is mutated, potentially speeding up cell growth, the normal copy reins it back in. In the new study, researchers
sought to understand how the normal copy achieves this restraining effect.
Using a mouse-derived cell line, they engineered cells in which they could pair normal KRAS with various mutated forms of the gene. By treating the cells with a common cancer drug, they shut down normal KRAS, bringing production of the
normal KRAS protein to a halt. The result was a surge in cell growth — strong evidence that normal KRAS can offset the growth-spurring effects of mutant KRAS.
The researchers then examined the crystal structure of the KRAS protein to identify where the two parts of the dimer — each derived from one of the KRAS genes — meet and link up. They showed that a particular mutation in KRAS, dubbed
D154Q, can interfere with that connection.
The next phase of the study involved lines of human lung cancer cells in which KRAS was mutated or overabundant — either of which can supercharge cell growth. To these cell lines, researchers introduced either normal KRAS or KRAS normal in every aspect but one: the D154Q mutation. As expected, the lines receiving normal KRAS showed slower cell growth. The lines receiving D154Q-blemished KRAS, by contrast, continued to proliferate wildly. The clear implication
is that normal KRAS protein cannot blunt the harmful effect of mutant KRAS if the two proteins don't fuse to form a dimer. The researchers found the same effect in mice carrying grafts of human tumor cells. In the animals, tumors expressing
the normal KRAS protein grew significantly slower than those expressing KRAS with the D154Q abnormality.
Finally, researchers showed, mutant forms of KRAS are most dangerous — most likely to accelerate cell growth — when they exist as dimers. In both laboratory cell lines and animal models, the investigators found that when a mutated KRAS gene also
carries the D154Q mutation, its growth-promoting capacity is lessened. A mutant KRAS protein unable to dimerize is much less of a cancer threat than one that does dimerize.
"Our findings suggest that dimerization appears to be an essential aspect of KRAS's role within the cell," says Dana-Farber's Chiara Ambrogio, PhD, lead author of the study. Adds Jänne, "On the one hand, in the dimer formed by normal and mutant
KRAS, the normal portion counteracts the negative effect of the mutant portion. At the same time, we've shown that dimerization is critical for KRAS mutants to be fully oncogenic, or cancer-causing. This reliance on dimerization suggests that disrupting
dimerization with novel therapies may be an effective way of attacking some cancers at their root."
"This research by Dr. Jänne and the SU2C-American Cancer Society Lung Cancer Dream Team is potentially very important for some patients with lung cancer, opening new possibilities for treatment. These preliminary findings are very encouraging," said Sung
Poblete, PhD, RN, president and CEO of Stand Up To Cancer, which supported the research.
The other co-lead authors of the study are Jens Köhler, MD, of Dana-Farber and Zhi-Wei Zhou, PhD, of University of Texas Southwestern Medical Center. David Santamaria, PhD, of the University of Bordeaux, France, is a co-senior author. Co-authors are Raymond
Paranal, Jiaqi Li, Marzia Capelletti, PhD, Cristina Caffarra, PhD, and Shuai Li, MD, of Dana-Farber; Haiyun Wang, PhD, and Qi Lv, of Tongji University, China; Sudershan Gondi, PhD, John C. Hunter, and Jia Lu, PhD, of University of Texas Southwestern
Medical Center; and Roberto Chiarle, MD, of Boston Children's Hospital and the University of Torino, Italy.
The work was supported by a Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT17-15); the Gadzooks Fund; the Cammarata Family Foundation Research Fund; the US Department of Defense
(W81XWH-16-1-0106 to KDW); the Cancer Prevention and Research Institute of Texas; the National Natural Science Foundation of China (31571363 and 31771469); and by a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation.