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The changing landscape of targeting cancer mutations
James “Jamie” Christensen, chief scientific officer at Mirati since 2013, is responsible for drug discovery, translational research, drug manufacturing and companion diagnostics research. At Mirati, Jamie has led activities related to the discovery and advancement of the company’s clinical and preclinical programs. He has authored or co-authored over 140 peer-reviewed research articles in scientific journals including Science, Nature, Cancer Cell, Cancer Discovery, New England Journal of Medicine and many others.
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ithin the past 20 years, our understanding of cancer has transformed dramatically due, in part, to the sequencing of the first human genome.1 Subsequently, tens of thousands of cancer genomes have also been sequenced.1 These fundamental advancements in genomic research have strongly influenced how we approach discovering and developing new therapies. This research has defined a new era in oncology drug development and has given rise to therapies targeting specific gene alterations and protein targets that are critically involved in the growth and survival of cancer cells while sparing healthy cells.
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.