The Story of ARAF

How “outlier” patients may open doors to new cancer treatment strategies.

A 66-year-old former light smoker (less than five packs a year) with stage IV lung cancer – I’ll call her Alice – had not responded to a number of chemotherapies and had an unfavorable prognosis. She became part of a phase 2 clinical trial and received treatment with sorafenib – and her disease went into almost complete remission within two months. She was free of cancer symptoms and there was no progression in her tumor for the next five years while she continued on the treatment, until she finally relapsed and passed away.

Study investigators were puzzled by Alice’s case. She had the best response to sorafenib among all lung cancer patients in the clinical trial, even though she suffered from an adenocarcinoma – a type of cancer not known to respond to gene-altering therapies such as sorafenib. An analysis of the entire genome sequence in her tumor revealed no mutations in KRAS, DGFR, BRAF, HER2, PIK3CA, or other genes that were ordinarily the targets for sorafenib. But the investigators did find an altered version of the ARAF gene known as S214C. A separate analysis of lung cancer patients not in the study revealed ARAF mutations in 1 percent of tumors. Together, these findings made it likely that, in certain cancers, ARAF was a proto-oncogene – a normal gene that can become a cancer-triggering one (oncogene) with only a slight alteration in its genetic code.

ARAF mutations can alter the usual signals that enter cells

ARAF is known as a proto-oncogene – a normal gene that can become a cancer-triggering one (oncogene) with only a slight alteration in its genetic code. Alterations in the genetic code of ARAF can make it unable to break up GTP, thus forcing a cellular pathway to stay in the “on” position. This can result in continuous cell proliferation that can, in turn, develop into cancer. In the RAF family, ARAF and CRAF each require changes in two amino acids to become oncogenic – a rare event – while the BRAF gene requires a change in only one.

Also known as ARAF1, PKS, and PKS2, ARAF is a member of the RAF family – a group of genes that produce signaling proteins called kinases. The RAF family also includes the genes BRAF and CRAF, which also produce proteins that affect the RAS signaling pathway. A signaling pathway consists of a group of molecules in a cell that work together to control functions such as cell division and cell death. After the first molecule in this pathway receives a signal, it then activates another molecule. This sequence (or “cascade”) continues molecule to molecule until the cell function is completed. RAS proteins serve as switches that regulate cell responses to signals from outside the cell by turning the signaling pathway on and off. The pathway is turned on when the kinases bind to a molecule called GTP (guanosine triphosphate), and turned off by breaking up the GTP molecule. Any alteration in the genetic code of the kinase can make it unable to break up GTP, thus forcing the pathway to stay in the “on” position. This can result in continuous cell proliferation that can, in turn, develop into cancer. In the RAF family, BRAF genes are much more likely to shift into cancer mode; they require a change in only one amino acid to become oncogenic, while ARAF and CRAF require two.

Knowledge of how altered RAF genes may lead to cancer traces back to the landmark research of J. Michael Bishop and Harold E. Varmus, two brilliant minds whose paths could have easily led them to careers in the humanities instead of science. Bishop’s first love was music, and as a teenager he loved to sing and play piano at two small country churches in York, Pennsylvania, where his father served as pastor. His interest in science was sparked during high school when he became friends with a local doctor. Bishop would accompany the doctor during appointments with patients, and he also watched the physician perform surgery. The interest in medicine stuck, setting him on a path that led to a medical degree from Harvard University. He worked in virology research in the Boston area for a while, and then accepted a faculty position to continue his research at the University of California, San Francisco, in 1968.

ARAF mutations in cancer are rare

Mutations of ARAF have been detected in samples of tumors from patients with lung cancer and cancer of the bile duct. An analysis of lung cancer patients revealed ARAF mutations in 1 percent of tumors known as adenocarcinomas, which are malignant tumors formed from the linings of glands. Another assessment found mutations in the ARAF oncogene in 11 percent of the tumors in patients with bile duct cancer.

Varmus had a passion for fiction in his student days, but also had an interest in medicine sparked by his physician father. After earning a master’s degree in English literature at Harvard, he traded his novels for books on anatomy as a medical student at Columbia University. Following a stint in basic research at the National Institutes of Health (NIH) and as a surgeon in the U.S. Public Health Service, he joined Bishop in San Francisco as a postdoctoral fellow in 1970. It was a match made in research heaven.

Along with other researchers, Bishop and Varmus believed that cancer wasn’t the result of an “invasion” from outside the cell, but rather a gene gone bad within the cell. Over the course of some twenty years, the pair helped identify how the Rous sarcoma virus turned normal genes into cancer-triggering oncogenes in rats. The researchers found that mutations of the RAS gene (which got its name because the gene was first isolated from rats with sarcoma) were among the most prevalent genetic alterations in cancer. Since the makeup of tumors in rats is very similar to tumors in humans, this research had major implications in cancer treatment research. Bishop and Varmus received the highest possible honor for their paradigm-changing work: the Nobel Prize for Medicine or Physiology, which they shared in 1989 for their discovery of “the cellular origin of oncogenes.”

Findings in mutations on the RAS gene spearheaded by Bishop and Varmus led to the recognition that mutations in RAF oncogenes in the RAS pathway are implicated in approximately 30 percent of all human cancers. While ARAF is part of the RAF family, it has had a low profile in cancer; variations in its genetic code do not generally interfere with its usual role in normal cell growth and development. In a study published in the January 2015 issue of the professional microbiology journal APMIS, for example, not a single genome in 383 tumors harbored an ARAF mutation. But more recent research has shown that alterations in ARAF may interfere with drugs that focus on another RAF oncogene called BRAF. A 2014 study revealed an interesting effect of ARAF when a BRAF-produced kinase inhibitor was used to block cancer-triggering signals in the mitogen-activated protein kinase (MAPK) pathway, where important signals are transmitted between the surface and nucleus of a cell. ARAF reactivated the signals downstream in this pathway, thus promoting growth of tumorous cells. This finding supports efforts to target ARAF in certain RAS- and RAF-mediated cancers.

If only it were as simple as A-B-C

It has been shown that sorafenib, a therapy originally developed to inhibit other kinases such as CRAF, can inhibit the growth of tumors with ARAF mutations. Another study, in 2014, revealed that ARAF reactivated signals that had been previously blocked by a BRAF kinase inhibitor. So, in choosing therapies, the relationships between A, B, and C Raf kinases introduce some complexity, sometimes for better and sometimes for worse.

ARAF mutations have also been implicated in intrahepatic cholangiocarcinoma (iCCA) –a very aggressive cancer of the bile duct with a five-year survival rate of only 10 percent. In a January 2015 report published in Nature, genomic sequencing revealed damaging mutations in the ARAF oncogene in 11 percent of the tumors in 122 patients with iCCA. Findings on ARAF as well on novel gene fusions in this report yielded information that could be useful in therapeutic targeting. This is another demonstration of how systematic sequencing of cancer genomes can bring more elusive mutations out of hiding.

Without this kind of clinical detective work in the sorafenib study, Alice might have remained a footnote instead of a discovery that opened up a new possibility for cancer treatment. “If recurrent but rare mutations underlie cancer growth and [therapeutic] responsiveness, they are not likely to be statistically called out as a potential driver of cancer through a genome scan of several hundred or even thousands of cases because they are so rare,” noted David Carbone, M.D., the director of the Ohio State University Comprehensive Cancer Center-James Thoracic Oncology Program and senior author of the study that included Patient A. “But for the patents who do have their specific genetic mutations, having this information is critical.”

Hopefully, molecular profiling that reveals how active certain gene malformations are will become more standard in the future—and turn more “outliers” like Alice into designated targets for therapy.

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