The Story of KRAS

Sick rats held the first clue to the most common human oncogene.

In 1967, Werner H. Kirsten was a young pathologist working at the University of Chicago when he noticed something curious: he could transmit leukemia to rats with through samples taken from mice with leukemia. This suggested the presence of a microscopic transmitting agent, such as a virus. Through further studies, Kirsten was not only able to confirm this observation, but prove that the same virus – later named the Kirsten sarcoma virus – did, in fact, induce sarcoma in rats.

This discovery was the first glimpse of the RAS family of genes. Twenty-years later, KRAS and HRAS were established as human oncogenes. An oncogene is a kind of abnormal gene that predisposes cells to develop into cancers. Unlike normal genes, which can be “turned off” after being “turned on,” oncogenes are forever stuck in the “on” position. The KRAS gene, also known as the Kirsten rat sarcoma viral oncogene homolog, was named in memory of Professor Kirsten.

The KRAS gene provides instructions for making a protein, also called KRAS, that is primarily involved in regulating cell division. In healthy cells, signals instruct the cell to grow and divide or to mature and take on specialized functions. KRAS is part of a signaling pathway – a cascade of cellular events that trigger one another like toppling dominos – known as the RAS/MAPK pathway. In this pathway, the KRAS protein relays signals from outside the cell to the cell’s nucleus.

A mutated KRAS gene promotes cancer not only by driving cell growth but also by silencing and deactivating protective tumor suppressor genes. Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die. When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer.

KRAS mutations can cause the cell to divide out of control.

KRAS is an oncogene, which means that it harbors the ability to cause cancer is otherwise healthy tissues with a a few simple edits to its DNA. And since the KRAS gene belongs to a family of GTPases – as in, it codes for a protein with the ability to cleave GTP – when it goes rouge, important instructions in cell division and growth get garbled.

Since KRAS was discovered more than 30 years ago, we know now that KRAS gene mutations occur frequently – so much so that the KRAS gene is understood to be the most common oncogene. Scientists have confirmed KRAS mutations in a broad range of cancers, including colorectal cancer, leukemia, lung cancer, and pancreatic cancer. Cancers with KRAS mutations are often particularly aggressive and hard-to-treat.

Most KRAS mutations are somatic, meaning they are acquired during the course of a person’s life and are found only in cells that become cancerous. However, one particular KRAS mutation, known as the KRAS-variant, is inherited. The KRAS-variant is a present in one out of every four people with cancer, linking it to more cancers than any other known inherited genetic mutation.

Given this, mutations in the KRAS gene are often an essential step in the development of many types of cancer. Primarily, when we talk about KRAS mutations, we’re discussing “activating” mutations: changes in the DNA that encodes a protein that results in a defective protein that is constitutively in the “on” position. This means that the protein cannot cleave a phosphate from the GTP molecule that is signaling the cell. Since the “on” signal from the GTP is never cleared by turning it into GDP, the Ras signaling pathway is unable to be turned off. This results in the cell receiving signals to grow and divide in an uncontrolled fashion, the hallmark of cancerous tissues. Somatic KRAS mutations (those acquired during a person’s lifetime) are implicated in lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, colorectal cancer, and leukemia, among other cancer types. KRAS mutations are found in over 90 percent of pancreatic carcinomas, a rate which far surpasses any other human tumor type regarding mutational frequency.

Discovered in 2008 by Joanne Weidhaas and Frank Slack, cancer researchers working at Memorial Sloan Kettering Cancer Center in New York City, the KRAS-variant has been shown to be a genetic marker of increased risk of developing premenopausal triple negative breast cancer, bi-lateral breast cancer, post-menopausal ovarian cancer, and non-small cell lung cancer. People with the variant have also been shown to be more likely to develop both breast and ovarian cancers or to develop multiple cases of cancer in their lifetimes. In general, KRAS-variant carriers tend to get aggressive and recurrent breast, ovarian, head and neck, lung, and pancreatic cancers.

Not long after their 2008 finding, Weidhaas and Slack founded MiraDX to develop a simple diagnostic test that uses blood or saliva samples to detect the presence of the KRAS-variant. The test was developed to help identify and diagnosis inherited cancers early on, when they are easier to treat; to help patients and their doctors be more vigilant about screenings; and, to make more informed decisions about therapies that may improve survival and quality of life.

Despite the fact that the KRAS-variant is so widespread, it is not usually part of regular genetic screening. However, it can be ordered by individual physicians, genetic counselors, or hospitals. Mirakind, MiraDx’s sister non-profit organization, also offers the test to participants in studies conducted by the organization to determine prevention strategies for individuals with the KRAS-variant, as well as for other similar genetic mutations.

There are many treatments that people with KRAS mutations may benefit from. However, despite intensive research investments in developing treatments that specifically target the KRAS gene, no such targeted treatments exist today. However, scientists in the biotech and pharmaceutical industries, as well as academic laboratories, continue to pursue treatment approaches that directly target the abnormal gene – many clinical trials for people with a KRAS mutation are now enrolling patients. Scientists are also attempting to target proteins that act downstream of KRAS. This is because a large body of evidence suggests that mutations in KRAS work together with other genes as part of cell networks, and that some of these other genes can be targeted by drugs.

 

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