Cancer expert, Melissa Johnson, MD, discusses the elusive KRAS target and the importance of providing patients choices that can offer sustained targeted inhibition. Watch more of her discussion below.
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Story Topic: KRAS
The changing landscape of targeting cancer mutations
As a scientist, I have a unique opportunity to participate in advancing targeted oncology into a meaningful and highly impactful area of scientific development. Today, there are more than 50 FDA-approved targeted drugs for cancers with known driver mutations, and research advances are rapidly increasing the options to target cancer mutations.2
One important first step in identifying cancer drug targets and developing targeted therapies is to understand the underlying genetic basis of cancer causation and progression at a molecular and cellular level. The genomic era in cancer research has ushered in a principle called “oncogene addiction.” Oncogene addiction is defined by the dependency of certain tumor cells on a single activated oncogenic protein or pathway to maintain their malignant properties, despite the presence of multiple mutations that contribute to tumor progression.3 In other words, we are trying to identify a cancer drug target gene or protein that acts as the Achilles’ heel of each cancer. Some targets are more difficult to drug than others–it took close to 4 decades from the initial discovery of KRAS before the first drug candidate showed promising clinical efficacy in a subset of patients with KRAS-mutated cancers.4 This showed us that, while difficult, targeting KRAS wasn’t impossible.
At Mirati, our scientific discovery and preclinical research seeks to understand the KRASG12C mutation on a holistic level with the purpose of better understanding its pathway, lifecycle and potential resistance mechanisms. These insights have informed our initial drug design strategy and will continue to influence our clinical development strategy toward optimizing the potential clinical benefit to patients. Our research in KRASG12C has also led to important and exciting learnings in other areas of KRAS, including KRASG12D. Our science-driven focus on drug discovery and development is based on the principle that all aspects of the mutation and cancer biology need to be understood and targeted with precision.
The targeted oncology landscape is rapidly evolving, and the development of these therapies has dramatically changed the way we approach discovery and research.2 There is still much more to address, including drug resistance mechanisms and finding better sequential therapies or combination.
In many ways, oncology research and development is leading the way toward the promise of patient-centric, personalized medicines, and I anticipate we will be at the forefront of this research with the goal of developing targeted therapies across many difficult to treat cancer mutations.
References:
- The Human Genome Project. National Human Genome Research Institute. Updated December 22, 2020. Accessed June 9, 2021.
- Targeted cancer therapies. National Cancer Institute. Updated June 7, 2021. Accessed June 9, 2021.
- Mahadevan D, Talavera F, El-Deiry Targeted cancer therapy. MedScape. Updated April 9, 2021. Accessed June 9, 2021.
- Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771-785.
KRASG12C proteins don’t quit
About one-quarter of patients with non-small cell lung cancer (NSCLC) have a KRAS mutation, and G12C mutations make up about 14 percent of them. KRASG12C mutations are also found in many other difficult to treat cancers, and are historically associated with poor prognosis.2,3
“Despite advancements in the treatment of cancer, patients with a KRASG12C mutation are still in need of a targeted treatment with improved responses and sustained durability,” said Joseph Leveque, chief medical officer, Mirati Therapeutics, Inc. “KRAS mutations are found in an aggressive subset of cancers that have minimal treatment options. Although first generation KRAS inhibitors bind to and irreversibly inhibit the KRASG12C mutated protein, it is an underappreciated observation that new KRASG12C proteins regenerate every 24-48 hours. Thus, continuous drug levels and persistent inhibition of the KRASG12C mutant protein is needed to achieve maximum antitumor activity.”
Leveque continued, “It’s not enough to just turn KRAS mutants off transiently. The good news is the science is still evolving and new research may shed light on how to further optimize targeting these mutations in difficult to treat cancers.”
Despite advancements in the treatment of cancer, patients with a KRASG12C mutation are still in need of a targeted treatment with improved responses and sustained durability
Mirati launched KRAS Regeneration — a healthcare professional campaign in part to raise awareness of the KRASG12C mutation and what is needed to overcome the insidious nature of the mutation.
Visit KRASRegeneration.com to learn more.
References
- Chien, Shanley. Targeting the KRAS mutation for more effective cancer treatment. MDAnderson.org. Published February 12, 2021.
- Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021; 384(2):185-187.
- Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: Striking a moving target. JCI Insight. 2018;3(15):e120858.