Philip A. Philip, MD, PhD
Nearly 35 years after its discovery as the first human oncogene, RAS
remains a frustrating target in anticancer therapy even as knowledge about the molecular drivers of malignancies continues to expand at a rapid pace. Thus far, no therapies aimed directly at RAS
mutations have been developed.
Nevertheless, a concerted effort by the National Cancer Institute (NCI) is starting to unravel the RAS
mystery by building the scientific foundation for researchers to move forward. Researchers are producing a more detailed roadmap of the cellsignaling networks set into motion by mutations in the gene along with a more accurate databank for mutations in the 180 genes in the pathway. Notably, a new method for producing a key RAS
protein from insect cells has yielded higher-quality material for experiments.
The focus on RAS
is understandable, considering its important role in tumorigenesis. More than 30% of all tumors have some sort of mutation in the RAS
family of genes, according to Sara Hook, PhD, RAS program officer at the NCI.
“If we had effective inhibitors to RAS
, or the RAS
pathway, it could radically change cancer treatment just because of the sheer volume of patients who would be affected,” Hook said in an interview with OncologyLive
From Rats to Humans
The observation that RAS
genes could cause cancer was initially discovered in rat sarcomas; hence the name, RA for rat and S for sarcoma. These genes were later identified in humans in 1982. RAS
is a family of oncogenes that are present in all cells in the body and were the first oncogenes identified in human cancer cells.1
Oncogenes work as an on/off switch for cell division, and RAS
mutations affect this switch, not allowing the cells to switch off and causing them to grow uncontrollably, leading to the development of cancer.
“In normal cells, the RAS
gene is under very tight control in terms of how it behaves, but in the cancer cell, when it’s mutated, it becomes out of control. It’s independently sending signals to the nucleus to not only make cells divide and proliferate without any control, but also to spread and evade the effects of anticancer drug therapy,” Philip A. Philip, MD, PhD, explained in an interview. Philip is leader of GI and Neuroendocrine Oncology, and vice president of Medical Affairs at the Barbara Ann Karmanos Cancer Center in Detroit.
There are three RAS
genes in humans: KRAS
, and NRAS
. Mutations within KRAS
are found more often in human cancers than are mutations within HRAS
.1 Stephen et al wrote in 2014 that KRAS
mutations may be more effective in oncogenesis than HRAS
because of its structure. Only KRAS has “stemlike properties” on certain cell types. KRAS
also seems to be critical in development.1 Mice that were lacking KRAS
died during formation of the embryos, while those that did not have HRAS
did not die at that stage. KRAS
is found to be more frequently altered in solid tumors: 95% of pancreatic cancers, 45% of colorectal cancers, and 35% of lung cancers, according to the NCI (Figure)
. By contrast, NRAS
is found to be more frequently altered in hematological cancers: 30% of acute myeloid leukemias and 15% of melanomas. HRAS
is found to be altered in 15% of bladder cancer.
oncogenes are the worst oncogenes,” Frank McCormick, PhD, FRS, DSc (Hon), national program advisor for the NCI’s RAS
Initiative, has said. McCormick is a professor emeritus at UCSF Hellen Diller Family Comprehensive Cancer Center in San Francisco.
The Research Bandwagon
mutations were initially discovered, there was a flurry of research into new drug possibilities, but these did not lead to effective treatments. Initially, there was hope that farnesyltrans- ferase inhibitors (FTIs) were the answer. However, testing found that, although FTIs did block HRAS
, the strategy did not prove effective in phase II trials for lung and pancreatic cancers, or in phase III trials for colorectal and pancreatic cancers.2
“There were some clinical trials in the early 2000s that did not succeed,” Hook said. Researchers found that the RAS protein already had an escape mechanism, she explained, and that the cells had found a way to get around the drugs.