Glen Campbell, a notable member of The Wrecking Crew, once commented on his decade-long journey to becoming an overnight success in 1967, largely due to John Hartford. This concept of a prolonged effort culminating in sudden recognition is mirrored in recent advancements in biomedical research, particularly concerning the case of daraxonrasib as a treatment for pancreatic cancer. Pancreatic cancer ranks as the fourth leading cause of cancer-related deaths in the United States, with an estimated 67,530 diagnoses and 52,740 deaths expected in 2026. The 5-year relative survival rate for advanced pancreatic cancer patients is a mere 3%. Nevertheless, this new drug is rapidly changing the landscape of clinical oncology:
Comprehensive findings from the daraxonrasib clinical trial, conducted by the biotech company Revolutions Medicines, were revealed at the annual meeting of the American Society of Clinical Oncology. The study was also published in the New England Journal of Medicine.
In-depth analysis of the study data corroborated prior announcements made by the company in an April press release: Patients suffering from advanced pancreatic cancer who received daraxonrasib as a second-line treatment experienced a median overall survival of 13.2 months, compared to 6.7 months for those receiving standard chemotherapy. Statistically, daraxonrasib decreased the risk of death by 60% when compared to chemotherapy.
“Daraxonrasib will significantly impact treatment strategies,” declared Brian Wolpin, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute. He contributed to the study and presented the findings at ASCO.
“In the immediate future, this will establish a new standard treatment for patients. Over the longer term, this illustrates that we can progress beyond chemotherapy for this disease, highlighting that decades of scientific investment and research is finally yielding results,” he added.
The groundbreaking aspect of daraxonrasib lies in its target—the oncogene RAS. The mutated KRAS appears in nearly 90% of pancreatic cancers, as well as in colon, lung, and other cancers, but has proven to be a challenging target. To grasp the significance of this research, we must understand the role of RAS proteins within cells. While somewhat technical, RAS’s functions are more relatable than concepts like “puts and calls on Wall Street.” RAS proteins belong to a superfamily of small G-proteins that function as molecular switches regulating cell proliferation, a process that, when dysregulated, can lead to cancer progression. Here’s a brief overview of cell biology:
G-proteins become active when bound to GTP (an analog of ATP, yet not utilized as the cell’s “energy currency”). They possess an intrinsic GTPase activity that converts GTP to GDP. When in the GDP state, the protein is inactive, and the transition from GTP to GDP is energetically downhill and, thus, irreversible within the cell. This means the switch cannot simply be flipped back on. Accessory proteins known as GAPs (GTPase-activating proteins) hasten this transition, while GEFs (guanine nucleotide exchange factors) substitute GDP for GTP, reactivating the G-protein and restarting the cycle. The mutant KRAS originated as the Kirsten Rat sarcoma virus oncogene, contributing to cancer progression by fostering inappropriate cell proliferation. Additional mutations generally result in primary tumors and metastasis. Other RAS proteins also involve cell adhesion (Rap), motility (Rho), and intracellular trafficking (Rab, Arf). The G-protein switch enables cells to interpret signals from surroundings, dictated by the transition from active (GTP-bound: on) to inactive (GDP-bound: off).
For many years, the oncogenic KRAS was deemed an “undruggable” target. Research from Kevan Shokat’s group at the University of California-San Francisco debunked this notion, leading to the development of daraxonrasib. However, the journey was convoluted, representing a classic example of scientific progress characterized by numerous discoveries and detours that can only be truly appreciated in hindsight.
The initial revelation in this sequence illustrated that viral oncogenes are ordinary cellular proteins from a host, which can be hijacked by cancer-causing viruses and then mutated during the viral replication cycle. Following the infection of the host with the altered virus, cancer could ensue. Peyton Rous pinpointed Rous Sarcoma Virus as a catalyst for cancer in chickens back in 1916, receiving a Nobel Prize for his work fifty years later in 1966. In 1976, Harold Varmus and J. Michael Bishop discovered c-src (cellular src), which corresponds to the cancer-causing v-src (viral src), and were honored with a Nobel Prize in 1989. G-proteins were identified as trimeric signaling proteins in 1980 by Alfred Gilman and Martin Rodbell, earning them a Nobel Prize in 1994. The small monomeric G-proteins within the RAS superfamily emerged shortly thereafter. RAS was crucial for regulating cell proliferation, especially as the eukaryotic cell cycle was articulated from the 1980s onward. This research incorporated contributions from thousands of scientists, most of whom were funded by the National Institutes of Health and similar organizations worldwide, stressing the fundamental role of foundational research for the eventual arrival of daraxonrasib as a rational yet unforeseen development.
Returning to Kevan Shokat and his team, they published an insightful commentary in Nature Chemical Biology (October 2024), illustrating how scientific breakthroughs typically occur:
RAS family proteins are small GTPases that transition between an inactive GDP-bound state and an active GTP-bound state to communicate signals to downstream pathways. Although their pivotal role in driving cancer has been recognized since the early 1980s, RAS proteins were considered virtually undruggable until quite recently. This contrasts sharply with the highly ‘druggable’ class of cancer drivers, protein kinases, which also bind to nucleotide triphosphates.
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The early 2000s witnessed a wealth of cancer genomic information, notably revealing the most common RAS mutation in lung cancer—KRAS(G12C). The cysteine amino acid is highly reactive, and this mutation offered a chemical target adjacent to the nucleotide pocket and key areas of RAS critical for cancer signaling. In 2013, our lab published a proof-of-concept demonstrating KRAS inhibition by directly targeting the mutant cysteine of oncogenic KRAS(G12C), starting through a disulfide tethering fragment-based screen (Fig. 1). Over the next ten years, KRAS-targeted preclinical and clinical drug development boomed, culminating in the expedited US Food and Drug Administration (FDA) approval of two KRAS(G12C) inhibitors for lung cancer, alongside over 30 RAS inhibitors currently undergoing clinical trials (Supplementary Table 1; gene in italics, protein in plain text).
Much within this discussion may seem obscure to those outside biochemistry. However, a pivotal element is that the mutant KRAS contains the amino acid cysteine (C) at position 12 of its protein chain instead of glycine (G). Cysteine’s unique reactivity, due to its sulfhydryl group (-SH), allows it to interact with various reactive compounds, some of which can inhibit KRAS activity. In contrast, the normal RAS gene contains glycine (-H), which does not react under biological conditions. Subsequent advances elucidated how to create a multi-component inhibitor for KRAS-GTP in its active conformation, giving rise to daraxonrasib. Yet, this achievement was not assured:
The designation of RAS as the most mutated oncogene often garners attention from funding agencies, but the feasibility of specific approaches typically dictates funding decisions. Despite recognizing the mutant cysteine’s advantages, our original funding application faced slim odds of success. Fortunately, we obtained support focused on individual researchers rather than the precise project. In particular, the flexibility of Howard Hughes Medical Institute funding was crucial for embarking on this ambitious journey with hopes of groundbreaking findings.
While such individual support fosters a culture of innovation and enables high-risk, high-reward science, institutional and public funding remains vital. Access to cutting-edge equipment (like NMR, FACS, synchrotron beamline facilities) and resources (such as COSMIC, PubChem, and SGC databases), played a significant role in our success. [1] The unwavering encouragement from colleagues, passionate about RAS for decades—including Frank McCormick, Mariano Barbacid, Channing Der, Kevin Shannon, Julian Downward, Fred Wittinghofer, and Roger Goody—was perhaps even more crucial than funding, facilities, and databases.
Had Kevan Shokat and his team not received generous support from the Howard Hughes Medical Institute to pursue their shared inclination, progress might have stalled at inhibitors targeting the reactive cysteine in KRAS. Instead, daraxonrasib is now available as a promising new treatment for pancreatic cancer. While it’s not a cure, this second-line treatment offers hope to numerous patients and clinical oncologists alike. The meaningful life extension afforded by daraxonrasib might even provide patients with enough time for personalized cancer vaccines to work effectively (as previously discussed). Additionally:
The notion of ‘undruggable’ has transitioned from a discouragement to a call to action, frequently describing targets that have recently become druggable. Although the term has evolved, the perception remains. To successfully address traditionally undruggable targets, it’s imperative to assess scientific dogma with skepticism. Innovative approaches, advanced technologies, or simply a fresh perspective can revolutionize our understanding of well-studied proteins like RAS. As a scientific community, we must tackle these challenges with greater funding security and flexibility, emphasizing support for creative individuals and teams, while allowing leeway for well-reasoned yet risky projects. The innovative hub-and-spoke framework established by the US National Cancer Institute RAS Initiative has provided invaluable assistance over the past decade, revitalizing RAS drug discovery.
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It’s impossible to quantify the fortunate breaks we’ve experienced along the way, from the prevalence of the G12C mutation in lung cancer to the biophysical properties of this mutant and the fragment library we screened (the top hits from our screening even influenced both FDA-approved G12C inhibitors). One of the most gratifying moments came in 2020 when Jon treated his first patient with KRAS(G12C)-mutant lung cancer and could share with Kevan and Ulf the dramatic response the patient had to a KRAS inhibitor. Together, we have been fortunate to witness the complete journey of KRAS drug development, from discovering initial hits in a fragment screen to observing patient benefits in clinical settings. However, despite significant strides with direct RAS inhibitors, we have yet to fully exploit their potential. As we start to see effective outcomes against non-cysteine RAS mutants and in other RAS-driven cancers, combined with ongoing refinement of combination therapies, it is evident that the best is yet to unfold.
The swift success of daraxonrasib reflects years of dedication and discovery.
Another essential lesson gleaned from the extensive series of findings leading to daraxonrasib emphasizes that virtually every scientific achievement in biology and biomedical science unfolds incrementally. Paradoxically, the term “incremental” often becomes a mark of disdain in peer reviews. This perception is primarily rooted in the fact that every protein carries with it over 2.5 billion years of evolutionary history. Evolution is a process of a tinkerer, not an engineer (think about the GAPs and GEFs mentioned earlier as ad hoc modifications that allow fine-tuning of the system). Had conventional wisdom been adhered to, the incremental advancements noted here may well have stagnated long ago. Kevan Shokat and his research team accurately identified the chemically reactive mutant as a key point of attack against KRAS. Their contributions, alongside those of recognized and respected colleagues, emphasize the importance of fostering scientific progress. In a brief introduction to a Chemical Reviews special issue titled “Drugging the Undruggable,” Shokat and Ziyang Zhang remarked, “To this day, the word ‘undruggable’ has yet to appear in any major dictionary. We hope it never does.” A sentiment shared by many, including former Senator Ben Sasse from Nebraska and countless pancreatic cancer patients and their families.
As we reflect on the current funding climate, it raises a pertinent question: Is the RAS Initiative at the Frederick National Laboratory for Cancer Research in Maryland considered a “scientific priority” by the current administration? These priorities will likely influence future support for “high-priority, gold-standard” scientific endeavors. Once again, we can only hope.
However, this should not be the case. It’s important to acknowledge that no one can predict in advance where the most crucial advancements will emerge; that’s precisely why experiments are conducted. The crux of the matter lies in whether we can secure funding for these experiments. The unknowable opportunity costs of forgoing these initiatives could be enormous. For example, only a quarter of our celebrated F-35s are fully mission-capable at any given moment (F-35 readiness stats). If merely 25% of our experiments yield results, we stand to gain significant benefits at a substantially lower total cost. Furthermore, the “failed” experiments can provide valuable insights, revealing mechanisms inconsistent with expectations. In stark contrast, the 75% of F-35s idling in hangars merely represent surplus materials.
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[1] This top-tier equipment is largely funded by the indirect costs (overhead) associated with NIH support, which have stirred political discourse over the past fifteen months. Absent this funding, the research would be impossible, given that many private organizations cap overhead to 10-15%. Thus, no scientist without NIH backing can access those generally smaller basic and clinical research grants.
