Portrait photo
Rohit Chandwani is a surgeon-scientist and an Assistant Professor of Surgery and Cell & Developmental Biology at Weill Cornell Medicine. His research focuses on understanding cell fate decisions in the pancreas through the lens of chromatin, particularly in the contexts of inflammation and tumorigenesis.
Portrait photo
Adrien Grimont is a former postdoctoral researcher in Rohit Chandwani’s lab at Weill Cornell Medicine, where he specialized in studying the interplay between RAS mutations and effector pathways in pancreatic cancer. He is continuing his work on KRAS biology as a senior scientist at Merus.

Advances in tumor mutational profiling, germline DNA sequencing and the development of organoid platforms to test various drugs on a patient’s tumor in vitro have brought to bear personalized medicine in cancer care. However, the scope of precision oncology in pancreatic cancer has been limited. Only a small minority of patients have been treated in a manner specific to their mutational context, as approximately 25% have actionable molecular alterations, and ‘matched’ therapies remain limited.1

The vast majority of patients harbor KRAS mutations and p53 alterations, a combination that yields poor outcomes and limited opportunities for tailored therapy.2-5 Though the most recent guidelines from the National Comprehensive Cancer Network advise molecular profiling for patients with advanced or metastatic pancreatic cancer, tumor features that drive treatment or even prognosis remain rare in Pancreatic Ductal Adenocarcinoma (PDAC).

With a 5-year median survival rate of 12.8 percent, PDAC is characterized by the high mutation rate of the proto-oncogene KRAS (95% of patients), with KRASG12D (35% of patients), KRASG12V (30%) and KRASG12R (15%) being the most common alleles.3-6 The KRASG12R mutation is unique as it seems to only occur in pancreatic cancer and not in the other cancer types associated with KRAS mutations, such as lung cancer or colon cancer.7-10 Several preclinical models suggest that KrasG12D and KrasG12V can initiate tumors in a similar manner, but KrasG12R appears to be deficient in its ability to initiate pre-malignant pancreatic intraepithelial neoplasia (PanIN).8,11-13 Whether the divergent biology of KrasG12R PDAC in mouse models extends to human disease has remained largely unknown.

To understand how mutations affect the behavior of pancreatic tumors, a large database of 1,360 patients who had pancreatic tumors surgically removed at Memorial Sloan Kettering (MSK) was analyzed.14 In this collaboration between Weill Cornell Medicine, MSK and the Ontario Institute for Cancer Research, we show that KRAS mutations are clinically and biologically different in patients. Stratification of this cohort between early- and late- stage disease (stage I vs stage II-III, respectively) revealed key clinical differences such as a higher prevalence of early-stage disease in women and among those who received neoadjuvant chemotherapy (NAC) and radiation (NAR). Indeed, early-stage pancreatic cancer is associated with improved survival, decreased distant recurrence, but no change in local recurrence.

Genomic analysis of a part of this cohort uncovered that KRASG12R mutant PDACs are enriched in the early-stage subgroup and correlate with the absence of lymph node metastasis but not a difference in tumor size. Overall, KRASG12D was associated with aggressive cancer and the worst outcomes, while KRASG12R and KRASG12V were associated with better overall survival. Patterns of recurrence also differed by allele: KRASG12R tumors showed a higher rate of local recurrence, while distant recurrence was most common in KRASG12D disease.

The distinct outcomes in patients by KRAS mutation were validated across multiple patient cohorts and associated with biological differences, with KRASG12D tumors showing more evidence of epithelial-mesenchymal transition and fewer inflammatory features. KRASG12R, by contrast, shows a reduction in oncogenic signaling in bulk RNA-sequencing, a paucity of immune cell-rich niches in spatial analyses, and decreased migratory behavior and improved survival in organotypic models. Together these data support the notion that the distinct subset of human KRASG12R-mutant pancreatic cancer is both clinically and biologically unique. 

This study presents valuable insight with direct prognostic relevance, and emphasizes the importance of mutational profiling to define biological variation among patients. These findings suggest that there should be a greater benefit of resection (i.e. local control) in KRASG12R patients for whom distant recurrence is less likely, whereas in the context of KRASG12D disease, systemic treatments might prove more favorable. The distinct clinical and molecular features associated with each KRAS mutant could be used in this way to stratify patients not only for current treatment modalities but in future precision oncology-based strategies, such as emergent KRAS inhibitors that increasingly demonstrate therapeutic promise.15-17 

References

  1. Pishvaian MJ, Blais EM, Brody JR, Lyons E, DeArbeloa P, Hendifar A, Mikhail S, Chung V, Sahai V, Sohal DPS, Bellakbira S, Thach D, Rahib L, Madhavan S, Matrisian LM, Petricoin EF 3rd. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020 Apr;21(4):508-518. doi: 10.1016/S1470-2045(20)30074-7. Epub 2020 Mar 2. Erratum in: Lancet Oncol. 2020 Apr;21(4):e182. doi: 10.1016/S1470-2045(20)30177-7. PMID: 32135080; PMCID: PMC7453743.
  2. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Wani S, Wilson PJ, Markham E, Cloonan N, Anderson MJ, Fink JL, Holmes O, Kazakoff SH, Leonard C, Newell F, Poudel B, Song S, Taylor D, Waddell N, Wood S, Xu Q, Wu J, Pinese M, Cowley MJ, Lee HC, Jones MD, Nagrial AM, Humphris J, Chantrill LA, Chin V, Steinmann AM, Mawson A, Humphrey ES, Colvin EK, Chou A, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Pettitt JA, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, Graham JS, Niclou SP, Bjerkvig R, Grützmann R, Aust D, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Falconi M, Zamboni G, Tortora G, Tempero MA; Australian Pancreatic Cancer Genome Initiative; Gill AJ, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Pearson JV, Biankin AV, Grimmond SM. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015 Feb 26;518(7540):495-501. doi: 10.1038/nature14169. PMID: 25719666; PMCID: PMC4523082.
  3. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grützmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM; Australian Pancreatic Cancer Genome Initiative; Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24. PMID: 26909576.
  4. Qian ZR, Rubinson DA, Nowak JA, Morales-Oyarvide V, Dunne RF, Kozak MM, Welch MW, Brais LK, Da Silva A, Li T, Li W, Masuda A, Yang J, Shi Y, Gu M, Masugi Y, Bui J, Zellers CL, Yuan C, Babic A, Khalaf N, Aguirre A, Ng K, Miksad RA, Bullock AJ, Chang DT, Tseng JF, Clancy TE, Linehan DC, Findeis-Hosey JJ, Doyle LA, Thorner AR, Ducar M, Wollison B, Laing A, Hahn WC, Meyerson M, Fuchs CS, Ogino S, Hornick JL, Hezel AF, Koong AC, Wolpin BM. Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma. JAMA Oncol. 2018 Mar 8;4(3):e173420. doi: 10.1001/jamaoncol.2017.3420. Epub 2018 Mar 8. Erratum in: JAMA Oncol. 2019 Apr 1;5(4):579. doi: 10.1001/jamaoncol.2019.0286. PMID: 29098284; PMCID: PMC5844844.
  5. Shoucair S, Habib JR, Pu N, Kinny-Köster B, van Ooston AF, Javed AA, Lafaro KJ, He J, Wolfgang CL, Yu J. Comprehensive Analysis of Somatic Mutations in Driver Genes of Resected Pancreatic Ductal Adenocarcinoma Reveals KRAS G12D and Mutant TP53 Combination as an Independent Predictor of Clinical Outcome. Ann Surg Oncol. 2022 Apr;29(4):2720-2731. doi: 10.1245/s10434-021-11081-z. Epub 2021 Nov 18. PMID: 34792696.
  6. Cancer Genome Atlas Research Network. Electronic address: andrew_aguirre@dfci.harvard.edu; Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017 Aug 14;32(2):185-203.e13. doi: 10.1016/j.ccell.2017.07.007. PMID: 28810144; PMCID: PMC5964983.
  7. SEER [Internet]. [cited 2024 Jun 10]. Cancer of the Pancreas - Cancer Stat Facts. Available online: https://seer.cancer.gov/statfacts/html/pancreas.html
  8. Zafra MP, Parsons MJ, Kim J, Alonso-Curbelo D, Goswami S, Schatoff EM, Han T, Katti A, Fernandez MTC, Wilkinson JE, Piskounova E, Dow LE. An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants. Cancer Discov. 2020 Nov;10(11):1654-1671. doi: 10.1158/2159-8290.CD-20-0442. Epub 2020 Aug 12. PMID: 32792368; PMCID: PMC7642097.
  9. Hobbs GA, Baker NM, Miermont AM, Thurman RD, Pierobon M, Tran TH, Anderson AO, Waters AM, Diehl JN, Papke B, Hodge RG, Klomp JE, Goodwin CM, DeLiberty JM, Wang J, Ng RWS, Gautam P, Bryant KL, Esposito D, Campbell SL, Petricoin EF 3rd, Simanshu DK, Aguirre AJ, Wolpin BM, Wennerberg K, Rudloff U, Cox AD, Der CJ. Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer. Cancer Discov. 2020 Jan;10(1):104-123. doi: 10.1158/2159-8290.CD-19-1006. Epub 2019 Oct 24. PMID: 31649109; PMCID: PMC6954322.
  10. Grabski IN, Heymach JV, Kehl KL, Kopetz S, Lau KS, Riely GJ, Schrag D, Yaeger R, Irizarry RA, Haigis KM. Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum. Cancer Epidemiol Biomarkers Prev. 2024 Jan 9;33(1):158-169. doi: 10.1158/1055-9965.EPI-23-0262. PMID: 37943166; PMCID: PMC10841605.
  11. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003 Dec;4(6):437-50. doi: 10.1016/s1535-6108(03)00309-x. PMID: 14706336.
  12. Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, Pérez-Gallego L, Dubus P, Sandgren EP, Barbacid M. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007 Mar;11(3):291-302. doi: 10.1016/j.ccr.2007.01.012. PMID: 17349585.
  13. Habbe N, Shi G, Meguid RA, Fendrich V, Esni F, Chen H, Feldmann G, Stoffers DA, Konieczny SF, Leach SD, Maitra A. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18913-8. doi: 10.1073/pnas.0810097105. Epub 2008 Nov 21. PMID: 19028870; PMCID: PMC2596215.
  14. McIntyre CA, Grimont A, Park J, Meng Y, Sisso WJ, Seier K, Jang GH, Walch H, Aveson VG, Falvo DJ, Fall WB, Chan CW, Wenger A, Ecker BL, Pulvirenti A, Gelfer R, Zafra MP, Schultz N, Park W, O'Reilly EM, Houlihan SL, Alonso A, Hissong E, Church GM, Mason CE, Siolas D, Notta F, Gonen M, Dow LE, Jarnagin WR, Chandwani R. Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer. Cancer Cell. 2024 Sep 9;42(9):1614-1629.e5. doi: 10.1016/j.ccell.2024.08.002. Epub 2024 Aug 29. PMID: 39214094; PMCID: PMC11419252.
  15. Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, Lee B, Orlen M, Tian S, Stalnecker CA, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Muonio K, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs WP, Hibshman PS, Amparo AM, Hennessey C, Rees MG, Ronan MM, Roth JA, Brodbeck J, Tomassoni L, Bakir B, Socci ND, Herring LE, Barker NK, Wang J, Cleary JM, Wolpin BM, Chabot JA, Kluger MD, Manji GA, Tsai KY, Sekulic M, Lagana SM, Califano A, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Lowe SW, Badgley MA, Aguirre AJ, Vonderheide RH, Stanger BZ, Baslan T, Der CJ, Singh M, Olive KP. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024 May;629(8013):927-936. doi: 10.1038/s41586-024-07379-z. Epub 2024 Apr 8. PMID: 38588697; PMCID: PMC11111406.
  16. Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8. PMID: 38589574; PMCID: PMC11111408.
  17. Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C, Menard M, Brodbeck J, Chen Z, Wei X, Rosen MJ, Gindin Y, Lee BJ, Evans JW, Chang S, Wang Z, Seamon KJ, Parsons D, Cregg J, Marquez A, Tomlinson ACA, Yano JK, Knox JE, Quintana E, Aguirre AJ, Arbour KC, Reed A, Gustafson WC, Gill AL, Koltun ES, Wildes D, Smith JAM, Wang Z, Singh M. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024 Jun 3;14(6):994-1017. doi: 10.1158/2159-8290.CD-24-0027. PMID: 38593348; PMCID: PMC11149917.

Media Inquiries

Mary Ellen Hackett
Manager, Communications Office
301-401-8670