Abstract IA008: Pancreas cancer: Genomics, RAS therapeutics and clinical landscape

Abstract Pancreatic adenocarcinoma (PDAC) is a highly challenging malignancy. Major developments in understanding the pathobiology, genetic makeup and immune morphology of this disease have accrued over the last several decades and these fundamental underpinnings are translating to improvements in survival in this disease. Genomically, PDAC is characterized by near ubiquitous activation in the MAPK pathway with KRAS mutations occurring at hotspots on exon 2, codon 12 and 13 (D, V, R) and more rarely on exon 3 (Q61) and exon 4 (146). Growth signals stimulate KRAS to enter an active GTP-bound state. Downstream pathway activations, include PI3K and RAF proteins, which translate active KRAS into signals for proliferation and survival.RAS mutations confer a highly immune suppressed tumor microenvironment in PDAC characterized by both immune evasion and notable for a dearth of effector activated T cells, predominance of T regulatory cells, myeloid infiltration, M2 macrophage and low rates of mismatch repair deficiency and other factors. KRAS mutations in PDAC confer an unfavorable prognosis relative to KRAS wild-type state. Allelic imbalance at KRAS loci in PDAC with gain of mutant copies of KRAS is associated with more advanced disease stage and adverse outcome. With revolutions in structural biology, chemistry, mathematics, bioengineering and related disciplines, a variety of agents have now entered the clinic which can effectively target RAS. Proof of principle targeting of KRAS G12C, which occurs in about 1% of PDAC, has been demonstrated with a variety of single agent covalent ‘off-state’ inhibitors. Other approaches to targeting RAS, include targeting the ‘on GTP bound’ state, proximal upstream and downstream targeting in the MAPK pathway, using protein degraders (PROTAC) and vaccine/immunotherapy approaches. For direct targeting both ‘allele specific’ and ‘pan (K)RAS’ targeted agents are in mid and phase development in PDAC. Signals of promising clinical activity with tri-complex multi-RAS ‘on-state’ inhibitors have been reported along with activity of PROTAC degraders and other allele specific and pan(K)RAS agents. The first phase III trial in PDAC compared to standard of care has completed enrolment and results are awaited. Other areas of promising proof-of-principle clinical signal include TCR targeting of PDAC in the setting of selected RAS mutations and HLA-dependencies along with vaccine immunotherapy in a minimal residual disease setting where early studies have demonstrated efficacy and safety. Challenges to this era of effective RAS targeting include identifying the best compounds to develop, selecting rational combinations to address both de novo and adaptive resistance and moving these therapeutics expeditiously through development given the major unmet medical need in PDAC. Citation Format: Eileen M. O'Reilly. Pancreas cancer: Genomics, RAS therapeutics and clinical landscape [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr IA008.