Breakthrough Expands Options in Precision Medicine
Introduction
Signal changes fuel cancer growth. KRAS is an essential signal found in both healthy and cancerous cells which creates challenges for drug development.
KRAS mutations are a driving force in some of the most aggressive cancers. For over 30 years countless dollars have been spent on many treatments using different tactics. Persistence has paid off and a world of breakthroughs are upon us.
Progress
When finding traditional exploits proved elusive, investigators began targeting changes to KRAS. Two major tactics have evolved, each with their own success:
- Targeting specific mutations or activated forms of KRAS.
- Stimulating an immune response against KRAS mutations.
Targeted Therapy:
KRAS can form a variety of changes including mutations called G12C, G12D, G12V, among others. Progress began against one form called KRAS G12C. Two drugs are now FDA approved which target KRAS G12C. Lumakras (Sotorasib) and Krazati (Adagrasib). For patients with lung or colon cancer carrying KRAS G12C mutations these drugs have a major impact by shrinking tumors, delaying progression, and improving survival. Drugs aimed at other mutations, such as G12D, remain in development.
Aside from site specific changes researchers are targeting another weakness – the activation of KRAS. A drug called RMC-6236 inhibits active forms of KRAS that often result from mutations. In an early clinical trial, RMC-6236 induced tumor shrinkage and stalls progression in patients with several mutations (G12D, G12V, G12S) in lung, colon, and pancreatic cancer.
Immunotherapy:
In another study, investigators at MSK developed a vaccine against specific forms of KRAS (G12D and G12R). The goal of this study was to prevent recurrence in high-risk individuals with late-stage colon or pancreatic cancer. By instigating an immune response, the mutation becomes an exploitable weakness helping the immune system recognize cancer cells. In responders to the vaccine, there was a delay in progression along with clearance or reductions of circulating DNA and bio markers. An immune response against KRAS could prevent relapse in some patients and might improve additional treatment for others. Some personalized vaccines also target KRAS making that approach a fruitful endeavor.
What can you do as a patient?
Ask your doctor about testing your tumor for genetic mutations. Some patients are met with resistance but highlight that rare mutations could impact care and might influence trial enrollment. This is especially important for late stage cancers where testing could uncover treatment options such as KRAS inhibitors. If the drugs mentioned above are not available, ask about similar strategies, off-label drugs, compassionate access, or other promising clinical trials.
How can we help people together?
Our goal is to help advance personalized medicine through access and advancement of innovative technology. Funding helps us engage devoted patients and fund grants toward researching new treatments.
Together, these advancements and new strategies against KRAS can lead to its defeat. New trials are underway that combine multiple drugs to prevent escape or increase efficacy. With time, we’ll learn optimal ways to hit KRAS mutations. In addition, novel strategies against partners of KRAS remain in development.