Medically reviewed by Susan Kerrigan, MD and Marianne Madsen
The KRAS protein
Cells contain many proteins that help in their development. The KRAS protein belongs to a group of oncogenes that help with cell growth, division, differentiation, and self-destruction. It does this by converting one molecule called GTP into another molecule called GDP. Many liken the process to a switch being turned on and off. The protein activates when it binds to a molecule of GTP and deactivates when it converts it to a molecule of GDP.
Mutation
As is the case with the development of most cancer cells, mutations occur when the KRAS protein gets stuck in the “on” position and remains activated. The protein then continues to instruct cells to reproduce, leading to uncontrolled clusters of cells that form KRAS-driven tumors.
KRAS mutations and cancer
KRAS mutations can be found in around 15-25% of all cancer tumors. The mutations are most commonly found in pancreatic cancers. However, they are also found in around 30-40% of colorectal cancer cases and 15-25% of lung cancer cases. KRAS mutations are somatic mutations, meaning they typically develop over a person’s lifetime, being more common in long-term tobacco smokers.
Treating a KRAS mutation
Most cancer patients, particularly lung cancer patients, will receive the same initial treatment irrespective of whether or not they have the KRAS mutation. This might involve a combination of surgery, radiation therapy, chemotherapy, or immunotherapy.
Typically, KRAS mutations have been considered non-actionable mutations, as they are resistant to most cancer treatments. For a treatment to be effective, cancer drugs usually bind to the surface of a protein. However, a KRAS protein has a smooth surface that doesn’t give them a place to do this. The result is that historically there has been no guaranteed way to treat KRAS mutations successfully.
Sotorasib
Medical researchers looking for new ways to treat KRAS mutations have shifted from finding ways to cure the mutation to instead finding ways to inhibit its development.
Around 80-85% of lung cancer cases are non-small cell lung cancer (NSCLC). Within this group, about 13% of patients will have a specific type of KRAS mutation called KRAS G12C.
Sotorasib, under its brand name Lumakras, is a recently developed KRAS inhibitor treatment that targets the KRAS G12C protein specifically. It works by attaching to the G12C protein, preventing the cancer cell from growing. The drug comes in pill form and is taken orally once a day. Phases 1 and 2 of the clinical trials of the drug were completed in 2020, and Amgen, the pharmaceutical company developing Lumakras, has already begun recruiting for a global phase 3 trial.
In February 2021, following the phase 2 results, the U.S. Food and Drug Administration (FDA) granted a Priority Review designation to the new drug to speed up the drug’s approval process. That approval was granted three months later, in May 2021, for a 960 mg dose. As part of the approval, the FDA requires a postmarketing study and trial to investigate whether a lower dose will offer similar clinical outcomes to the previous study. Lumakras has now become the first approved drug to target a previously drug-resistant lung cancer mutation.
It is still early to say that a solution has been found to treating KRAS mutations. However, this breakthrough is good news for thousands of lung cancer patients diagnosed with KRAS-driven cancer.
References
- KRAS gene: MedlinePlus Genetics
- KRAS and Lung Cancer
- Targeting the KRAS mutation for more effective cancer treatment
- What Is Lung Cancer? | Types of Lung Cancer
- Targeted Drug Therapy for Non-Small Cell Lung Cancer
- FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy | FDA