By Binod Dhakal, MD, MS
The year 1982 heralds the discovery of the first mutated genes to be identified in cancer, RAS. The three RAS genes — KRAS, NRAS, and HRAS — still constitute the most frequently mutated oncogene family in human cancers. However, despite more than three decades of effort, no effective RAS inhibitors have been developed. Thus far, RAS has been rendered an “undruggable” target, and it’s not alone in this category. Other known drivers, such as MYC and fusion transcription factors commonly seen with pediatric cancers have been deemed undruggable as well, owing to large protein-protein interaction interfaces or to the lack of deep protein pockets. Drugging these targets has been one of the key challenges to cancer research and a barrier to fully understanding tumor heterogeneity and resistance mechanisms. Despite the challenges, new concepts in drug development and a deeper understanding of synthetic interactions could ultimately pave the way to find potential agents for these targets.
These recalcitrant targets, acting as cancer villains for more than three decades, are somewhat like “Borg Ships” of “Star Trek,” making it impossible to surmount the enemy. However, the revolution in genomics is poised to change this status quo and enable us to understand the Achilles’ heel of these proteins. Soon we will have several small proteins and even antibodies targeting this enormous swath of proteins that conventional drugs simply can’t access. At this year’s ASH annual meeting, Drugging the Undruggable, a Special Scientific Symposium chaired by Kimberly Stegmaier, MD, of Dana-Farber Cancer Institute, will discuss several genomic- and chemistry-based approaches against these targets, as well as some challenges. She will discuss the application of genome-scale functional genomic screens to identify new “synthetic lethal” liabilities. David Solit, MD, of Memorial Sloan Kettering Cancer Center will discuss recent advances in precision medicine in oncology. Since every single patient with cancer exhibits a different genetic profile and that profile can change over time, “tailored” treatment rather than a one-size-fits-all approach, is likely to benefit patients, making it an attractive concept. The debate remains as to whether precision medicine is a mere concept or an assurance of a better future in oncology. Focusing on the prospective tumor/normal profiling at his institution, Dr. Solit will discuss the results and the insights gained from exceptional responders.
In the field of new therapeutics targeting cellular machinery, a technology making headlines is the use of Proteolysis Targeting Chimeras (PROTACs). PROTACs use an intracellular ubiquitin-proteasome system to induce targeted protein degradation. In March 2019, the first targeted protein degrader led by PROTACs hit the clinic for prostate cancer. Craig Crews, PhD, of Yale University will discuss the potential of PROTACs to enhance the druggable target space. He will also discuss the initial safety and tolerability data of the first two protein degraders on estrogen and androgen receptors. Based on the concept of “event-driven” pharmacology rather than the “occupancy-driven” mode of conventional small molecule inhibitors, PROTACs, though still in their infancy, could lead the target protein to attain loss-of-function via a transient binding event. Roughly 85 percent of the human proteome lacks enzymatic activity or functional interactions, making this space untouchable and a daunting initiative for drug development, until now. With an improved understanding of genomics and major strides made in the basic understanding of the biochemical and biological properties of these proteins, there is cautious optimism that what has been an impossible mission may become “Mission Possible” to develop drugs against the “undruggable.”
Dr. Dhakal indicated no relevant conflicts of interest.