At the time, co-lead author Dr. John Ferrarone was pondering the same observation in the human clinical data next door, as a medical oncology fellow working in the laboratory of co-senior author Dr. Harold Varmus, the Lewis Thomas University Professor of Medicine and a member of the Meyer Cancer Center. “My main interest in this project was more from a clinical angle, so I was interested in learning if there was a way to potentially exploit tumors with these common mutations,” said Dr. Ferrarone, who is now an instructor in medicine at Weill Cornell.
Teaming up with Dr. Varmus, Dr. Cantley, who is now at the Dana Farber Cancer Center, and additional collaborators across Weill Cornell and at other institutions, the researchers embarked on a deep dive into the way the products of the three genes behave in mouse models and cultured human cells. The group employed techniques that ranged from the cutting edge of genetic engineering, proteomics, metabolomics and mouse models to classical biochemical and cell biological experiments.
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“Using multiple approaches at the genetic, protein and metabolite level allowed us to obtain a more comprehensive understanding of what was going on within each species, and then try to cross-correlate and dissect where the disparities were between the two,” said Dr. Stein.
The multi-disciplinary approach pinpointed a crucial difference in regulation of glucose metabolism between mice and humans driven by LKB1, due to slight differences in the two species’ regulation of the metabolic enzyme triose phosphate isomerase (TPI1). As a result, mouse tumors that carry mutations in KRAS and TP53 gain a significant metabolic advantage by mutating LKB1 as well. But, in humans, mutating LKB1 in the same context appears to harm the tumor cells as they can no longer regulate TPI1 and glucose metabolism. That explains why the three mutations seldom occur together in human cancers.
“Taking out a master regulator enzyme can have very detrimental effects, so the discussions now are more about going downstream and targeting other molecules,” said Dr. Stein.
Nonetheless, he and Dr. Ferrarone are optimistic about the work guiding future drug discovery efforts. The new findings also sound a cautionary note for investigators relying heavily on mouse models to screen drug candidates, as compounds that might work well against human cancers could actually be missed in current murine tumor models.
Source: Eurekalert
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