The National Cancer Institute (NCI) has awarded a multi-principal investigator (MPI) R01 grant totaling nearly $3.4 million to Duke Pathology’s Hui-Kuan “Kevin” Lin, PhD, director of Prostate Cancer Research, and Hong-yu Li, PhD, professor of Pharmacology at the University of Texas at San Antonio, as co-principal investigators. The project brings together an interdisciplinary team, including co-investigator Shiaowen "David" Hsu, MD, PhD, professor in Duke’s Division of Medical Oncology, to advance a promising strategy for targeting some of the most challenging cancers.
At the center of the study, which is funded over the next five years, is Kirsten RAt Sarcoma viral oncogene homolog (KRas), one of the most mutated oncogenes in human cancer. Mutations in KRas are often found in highly aggressive pancreatic, lung, and colorectal cancers, which are associated with poor survival outcomes. Despite decades of research, effective treatment options for KRas-driven cancers remain limited, presenting a critical unmet need in oncology.
Lin and his collaborators aim to address this challenge by identifying previously unrecognized downstream effectors that are essential for the survival of KRas-mutant cancer cells. By targeting these key molecular pathways, the team hopes to develop effective therapies.
Moving Beyond Existing KRas Inhibitors
Recent advances in KRas-targeted therapy have led to the development of inhibitors such as AMG 510 (sotorasib), which has shown clinical efficacy and received FDA approval for certain lung cancers. However, these therapies are limited in scope. Mutations like KRasG12C, which AMG 510 targets, represent just a fraction of KRas-driven cancers. They account for approximately 13% of lung adenocarcinomas and an even smaller percentage of other tumor types.
“While these breakthroughs are encouraging, they reveal the need for broader strategies,” said Lin. “The majority of KRas mutations aren’t targeted by existing therapies.”
The newly funded project seeks to close this gap by shifting the focus from KRas itself to the downstream signaling pathways it activates. Although pathways such as MAPK and PI3K/Akt have long been implicated in KRas-driven tumor growth, combination therapies targeting these cascades have shown limited clinical success. This suggests that other important mediators have yet to be found.
Discovery of a Promising Lead Compound
A key breakthrough underlying this grant is the team’s identification of a novel compound referred to as #1a through extensive screening of more than 30,000 candidates. Early findings demonstrate that this compound selectively targets KRas-driven cancer cells while sparing normal cells, a critical feature for minimizing toxicity.
In multiple preclinical models—including xenografts, patient-derived xenografts (PDXs), and genetically engineered mouse models with diverse KRas mutations—compound #1a has shown potent anti-tumor activity.
Notably, it disrupts a newly identified downstream effector that appears to be essential for the survival of KRas-mutant cancer cells, triggering what researchers describe as “cancer cell catastrophe.” Equally promising, the compound has not demonstrated significant toxicity in animal models, highlighting its potential as a safe and effective therapeutic candidate.
A Transformational Research Approach
Lin and Li’s team will further evaluate compound #1a and its derivatives across a range of tumor models. Using advanced methodologies that include medicinal chemistry, genetic modeling, and translational cancer platforms, they aim to refine the compound’s efficacy and better understand how it works.
The project’s three specific aims will focus on:
- Validating the role of the newly identified KRas downstream effector
- Optimizing compound #1a and related molecules for therapeutic use
- Testing efficacy across diverse cancer models representing KRas-driven disease
This comprehensive approach reflects how innovative and ambitious this study is.
“Our goal is not only to develop a new therapeutic agent, but to fundamentally change how we think about targeting KRas-driven cancers,” said Lin. “By uncovering new biology, we hope to open the door to more effective and broadly applicable treatments.”
Broad Implications for Cancer Care
If successful, this research could mark a significant advance in the treatment of various KRas-driven cancers, long considered one of the most difficult areas of oncology. By moving beyond mutation-specific inhibitors and targeting a broader set of molecular vulnerabilities, the study has the potential to impact a wide range of tumor types.
The findings may also establish a new paradigm for cancer drug development, emphasizing the importance of downstream signaling networks and tumor-specific dependencies.
With a strong, collaborative team and a foundation of compelling early data, Lin’s NCI-funded project represents an exciting step forward in the pursuit of innovative cancer therapies and offers hope for patients facing KRas-driven disease.