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PREVALENCE
RAS IN
ONCOGENESIS
RAS MUTATIONS
CHALLENGES
IN PDAC
POTENTIAL OF
TARGETING RAS

Over 90% of patients with PDAC have tumors carrying a RAS mutation1

In pancreatic adenocarcinoma (PDAC)

Imagine loosening
 the grip of RAS

Given its pivotal role in PDAC,
RAS is an important therapeutic target1

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Over 90% of patients with PDAC have tumors carrying a RAS mutation1

  • Oncogenic RAS mutations are among the most common drivers of human cancers2,3
  • Even nonmutated wild-type RAS may play a role in oncogenesis4-6
  • Nearly all RAS mutations in PDAC occur at KRAS position G12, but RAS mutations in other isoforms and at KRAS positions G13 and Q61 are also observed1

When PDAC presents, expect RAS1

RAS is the key oncogenic driver of PDAC1,7

  • RAS proteins regulate cell growth by switching between the RAS(ON) and RAS(OFF) states3,8
    • In normal adult cells, RAS is predominantly in the inactive OFF state and is only transiently switched to the active ON state in response to growth signals9,10
  • Oncogenic RAS mutations increase the amount of RAS in the ON state, resulting in overactive RAS signaling and uncontrolled cell growth3,9

In PDAC, RAS mutations are thought to play an integral role in:

Icon of a cell and an arrow to represent initiation

Initiation

Oncogenic RAS mutation is an initiating genetic event in the development of PDAC7

Icon of one cell multiplying to represent progression

Progression

The resulting oncogenic RAS(ON) signaling drives tumor proliferation and cell survival4,7,11,12

Icon of a cell surrounded by lines in a circle to represent resistance

Resistance

Oncogenic RAS(ON) signaling may promote an immunosuppressive tumor microenvironment that can contribute to resistance to therapy12,13

Excessive RAS signaling may contribute to the difficulty of treating PDAC4,12,13

RAS mutations are highly heterogeneous1

A gene icon

KRAS, NRAS, and HRAS are the primary RAS isoforms.1,3

RAS mutations in PDAC1

Pie chart that shows the percents of the most common G12 mutations, including G12D (~40%), G12V (~29%), G12R (15%), G12C (<2%), and other (~15%)
  • ~85% of PDAC has a KRAS mutation at position G121
  • The KRAS G12D variant is the most common mutation in PDAC (~40%), followed by G12V (~29%) and G12R (~15%)1
  • The KRAS G12C variant is rare in PDAC (<2%)1

National Comprehensive Cancer Network® (NCCN®) recommends determining your patient's mutation status at PDAC diagnosis14

The NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma recommend molecular testing for patients with locally advanced/metastatic disease to identify potentially actionable somatic findings, including KRAS mutations using comprehensive genomic profiling.14‡

Targeting multiple RAS mutations is an opportunity to address unmet need in RAS-addicted PDAC

More effective treatment strategies for RAS-addicted PDAC are critically needed

Metastatic PDAC remains one of the most lethal forms of cancer, with a 5-year survival rate of about 3%15

Currently available treatments fall short in treating patients with PDAC

Chemotherapy provides limited clinical benefit
  • The median OS in patients receiving 1L chemotherapy for metastatic PDAC ranged from 8.5 months to 11.7 months16-22
  • The median OS in patients receiving 2L+ chemotherapy ranged from 6.1 months to 6.7 months23-29
Only a small subgroup of patients receive current targeted treatments
  • Fewer than 1 in 5 patients were eligible for approved targeted therapies and immunotherapies2,14,30-36
No RAS-targeted therapies are approved for PDAC37
  • PDAC's reliance on continued oncogenic RAS signaling highlights an unmet need for these patients1,4,7,11,12
  • Targeting multiple RAS mutations is an opportunity to address unmet need in RAS-addicted PDAC

Discover potential approaches to treat RAS-addicted cancers

Learn more  

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*Includes any NRAS mutation at positions G12, G13, or Q61.1

†Includes any mutation at this KRAS position.1

‡Tumor/somatic molecular profiling, preferably using a next-generation sequencing (NGS) assay, is recommended for patients with locally advanced/metastatic disease who are candidates for anticancer therapy to identify clinically actionable and/or emerging alterations. These alterations include, but are not limited to: fusions (ALK, NRG1, NTRK, ROS1, FGFR2, and RET), mutations (BRAF, BRCA1/2, KRAS, and PALB2), amplifications (HER2), microsatellite instability (MSI), mismatch repair deficiency (dMMR), or tumor mutational burden (TMB) using comprehensive genomic profiling via an FDA-approved and/or validated next-generation sequencing (NGS)–based assay, and HER2 overexpression via IHC ± FISH. RNA sequencing assays are preferred for detecting RNA fusions because gene fusions are better detected by RNA-based NGS. Testing on tumor tissue is preferred; however, cell-free DNA testing can be considered if tumor tissue testing is not feasible.14

1L=first-line; 2L=second-line; ALK=anaplastic lymphoma kinase; BRAF=B-Raf proto-oncogene, serine/threonine kinase; BRCA=breast cancer gene; DNA=deoxyribonucleic acid; FGFR2=fibroblast growth factor receptor 2; FISH=fluorescence in situ hybridization; HER2=human epidermal growth factor receptor 2; HRAS=Harvey rat sarcoma virus; IHC=immunohistochemistry; KRAS=Kirsten rat sarcoma virus; NRAS=neuroblastoma rat sarcoma virus; NRG1=neuregulin 1; NTRK=neurotrophic tyrosine receptor kinase; OS=overall survival; PALB2=partner and localizer of BRCA2; RAS=rat sarcoma virus; RET=ret proto-oncogene protein; RNA=ribonucleic acid; ROS1=ROS proto-oncogene 1, receptor tyrosine kinase.

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Cancer Discov. 2013;3(1):112-123. doi:10.1158/2159-8290.CD-12-0231 6. Zhou B, Der CJ, Cox AD. The role of wild type RAS isoforms in cancer. Semin Cell Dev Biol. 2016;58:60-69. doi:10.1016/j.semcdb.2016.07.012 7. Gurreri E, Genovese G, Perelli L, et al. KRAS-dependency in pancreatic ductal adenocarcinoma: mechanisms of escaping in resistance to KRAS inhibitors and perspectives of therapy. Int J Mol Sci. 2023;24(11):9313. doi:10.3390/ijms24119313 8. Singhal A, Li BT, O'Reilly EM. Targeting KRAS in cancer. Nat Med. 2024;30(4):969-983. doi:10.1038/s41591-024-02903-0 9. Waters AM, Der CJ. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med. 2018;8(9):a031435. doi:10.1101/cshperspect.a031435 10. Zhou Y, Hancock JF. Ras nanoclusters: versatile lipid-based signaling platforms. Biochim Biophys Acta. 2015;1853(4):841-849. doi:10.1016/j.bbamcr.2014.09.008 11. Gimple RC, Wang X. RAS: striking at the core of the oncogenic circuitry. 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