Targeting NRAS Oncoproteins for the Treatment of Melanoma

Martin McMahon, PhD

Cumming-Presidential Professor of Cancer Biology, Dept. of Dermatology & Huntsman Cancer Institute of the University of Utah

The photo depicts a metal sculpture of a RAS oncoprotein  sculpted by Dr. Bryan Welm. The use of two metals shows the dynamic conformational changes in the RAS protein which has facilitated the development of RAS-targeted therapies. Dr. Welm’s inspirational and artistic sculpture is now on display at the Huntsman Cancer Institute.  

Treatment of melanoma patients has been revolutionized by basic scientific discoveries in the laboratory, which have been translated into new therapeutics that have had a remarkable and positive effect on melanoma patient survival.  Among the most significant advances, immunotherapies such as anti-CTLA4 (Yervoy: FDA approved in 2011) that activate the patient’s immune system to target cancer cells are now the front-line treatment for most melanoma patients.  This approach, pioneered by Dr. James Allison and Dr. Tasuku Honjo,led to the award of the 2018 Nobel Prize in Physiology or Medicine. Moreover, the discovery that melanomas can be sub-grouped into distinct genetic categories has also led to the FDA approval of drugs such as vemurafenib (Zelboraf: FDA approved in 2011), which target the specific genetic damage that drives the irregular behavior of the BRAF-mutated subset of melanoma.  Despite these successes, major challenges remain, not the least of which aredrugs targeting that subset of melanomas driven by mutational damage to RAS oncoproteins, of which NRAS is commonly altered in melanoma.   

NRAS was first discovered in 1983 by two outstanding British cancer researchers, Dr. Chris Marshall and Dr. Alan Hall, both of whom died prematurely, with the connection between NRAS and melanoma made in 1984.  Moreover, NRAS is member of a family of RAS genes that are drivers of ~20% of all human cancers – corresponding to ~250,000 new cancer patient diagnoses in the USA every year.  In normal cells, RAS proteins function as molecular switches to turn on and off normal processes of cell proliferation (growth and division of cells).  However, genetic damage to RAS genes in cancer lock RAS oncoproteins in the on state – as if jamming a brick on the accelerator of a car, thereby unleashing the uncontrolled growth that is characteristic of many cancers, especially advanced melanoma.  Hence, targeting RAS oncoproteins has been a major priority of the academic and private sector cancer therapeutics community for over 40 years.  However, RAS proteins proved to be a tough nut to crack!!  Described variously as either a “greasy ball” or a “tennis ball”, RAS oncoproteins had no obvious nooks or crannies into which drugs might bind to block their cancer promoting activity.  Indeed, after many years of enormous investment, hard work and some false starts, some in the cancer research community had branded RAS oncoproteins as completely “undruggable” leading to pessimism, disappointment and disillusionment within the field.  However, the hero of this story is a U.C. San Francisco scientist: Dr. Kevan Shokat who, working with his UCSF collaborator, Dr. James Wells, had a clever idea to target a form of RAS that is commonly found in lung, colorectal or pancreatic cancer known as KRASG12C.  KRASG12C has a novel chemical handle to which drug-like molecules could be attached, and they reported the first such agents that blocked the oncogenic activity of KRASG12C in a seminal paper in Nature in 2013.  Stimulated by this work, scientists at both Amgen and Mirati Therapeutics (now Bristol Myers Squibb) invented two drugs: sotorasib (aka Lumakras) and adagrasib (aka Krazati) respectively that received FDA approval for the treatment of the KRASG12C subset of lung cancers in 2022.Importantly, the work from Shokat and colleagues at UCSF, and the scientists at Amgen and Mirati revealed new aspects of the structure and function of RAS oncoproteins that opened the floodgates for the development of new drugs that target RAS oncoproteins. Hence, the previously “undruggable” has now well-and-truly been drugged!!  Indeed, the pace of development of new RAS drugs is so fast that a review written today would likely be out-of-date within three months!   

So what prospect does all of this basic science and drug discovery offer for patients with NRAS-driven melanoma? For now, such patients will continue to receive immunotherapy, since that remains the front-line treatment for most melanoma patients. Unfortunately, many of those patients will either not respond to or ultimately progress on immunotherapy – and the current options for second-line therapy are quite limited and not particularly effective. However, with the advent and testing of new NRAS oncoprotein inhibitors in late-stage preclinical testing in the lab and in early-stage clinical trials, the prospect of effective NRAS-targeted second-line therapy is becoming a reality. Now the longer–term challenge for the melanoma research community is to come up with novel combinations of immunotherapy plus oncoprotein-targeted therapy that will not just control melanoma, but that will eradicate it completely.  

To that end, under the guidance of the Melanoma Research Foundation, a meeting was recently convened in Washington DC entitled, “Targeting RAS Signaling in Melanoma” in which experts and thought-leaders in the field discussed plans for tackling the problem of NRAS-mutated melanoma and began to come up with ideas for future combination therapies that will be first tested in the lab, with the most promising approaches advancing into clinical trials in melanoma patients. Although there is still much to be done, optimism within the melanoma research community is sky-high that we will soon be able to treat all forms of melanoma with the most up-to-date, effective and targeted therapies.  If there is a lesson in this remarkable story, it is that persistence in basic laboratory science is critical to overcoming even the most difficult challenges in cancer research.  Indeed, after 40 years of frustration, it looks like the challenge of targeting RAS oncoproteins in many types of cancer is finally close to being solved, offering potentially major implications for the treatment of patients with melanoma.