Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer-Reference-Cited by-同舟云学术

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer

Published:2024-07-08 Issue: Volume: Page:
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Dilly Julien¹^ORCID,Hoffman Megan T.¹^ORCID,Abbassi Laleh¹^ORCID,Li Ziyue¹^ORCID,Paradiso Francesca²^ORCID,Parent Brendan D.¹^ORCID,Hennessey Connor J.¹^ORCID,Jordan Alexander C.¹^ORCID,Morgado Micaela¹^ORCID,Dasgupta Shatavisha³^ORCID,Uribe Giselle A.¹^ORCID,Yang Annan¹^ORCID,Kapner Kevin S.⁴^ORCID,Hambitzer Felix P.¹^ORCID,Qiang Li⁵^ORCID,Feng Hanrong⁵^ORCID,Geisberg Jacob¹^ORCID,Wang Junning⁶^ORCID,Evans Kyle E.¹^ORCID,Lyu Hengyu⁷^ORCID,Schalck Aislyn²^ORCID,Feng Ningping²^ORCID,Lopez Anastasia M.²^ORCID,Bristow Christopher A.²^ORCID,Kim Michael P.²^ORCID,Rajapakshe Kimal I.⁸^ORCID,Bahrambeigi Vahid⁷^ORCID,Roth Jennifer A.³^ORCID,Garg Kavita⁹^ORCID,Guerrero Paola A.⁷^ORCID,Stanger Ben Z.¹⁰^ORCID,Cristea Simona⁵^ORCID,Lowe Scott W.¹¹^ORCID,Baslan Timour¹¹^ORCID,Van Allen Eliezer M.¹^ORCID,Mancias Joseph D.¹^ORCID,Chan Emily¹²^ORCID,Anderson Abraham¹³^ORCID,Katlinskaya Yuliya V.¹³^ORCID,Shalek Alex K.¹⁴^ORCID,Hong David S.⁷^ORCID,Pant Shubham²^ORCID,Hallin Jill¹⁵^ORCID,Anderes Kenna¹⁵^ORCID,Olson Peter¹⁵^ORCID,Heffernan Timothy P.¹⁶^ORCID,Chugh Seema¹^ORCID,Christensen James G.¹⁵^ORCID,Maitra Anirban⁸^ORCID,Wolpin Brian M.¹⁷^ORCID,Raghavan Srivatsan¹⁸^ORCID,Nowak Jonathan A.¹⁹^ORCID,Winter Peter S.¹⁴^ORCID,Dougan Stephanie K.¹^ORCID,Aguirre Andrew J.¹^ORCID

Affiliation:

1. Dana-Farber Cancer Institute, Boston, MA, United States

2. The University of Texas MD Anderson Cancer Center, Houston, TX, United States

3. Broad Institute, Cambridge, MA, United States

4. Dana-Farber/Harvard Cancer Center, Boston, United States

5. Dana-Farber Cancer Institute, Boston, United States

6. Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, United States

7. The University of Texas MD Anderson Cancer Center, Houston, Texas, United States

8. The University of Texas MD Anderson Cancer Center, United States

9. Resolution Bioscience, United States

10. University of Pennsylvania, Philadelphia, Pennsylvania, United States

11. Memorial Sloan Kettering Cancer Center, New York, New York, United States

12. Amgen (United States), Thousand Oaks, CA, United States

13. Amgen Inc., Thousand Oaks, CA, United States

14. Massachusetts Institute of Technology, Cambridge, MA, United States

15. Mirati Therapeutics (United States), San Diego, CA, United States

16. The University of Texas MD Anderson Cancer Center, Houston, United States

17. Dana-Farber/Harvard Cancer Center, Boston, MA, United States

18. Dana-Farber Cancer Institute, Boston, Massachusetts, United States

19. Brigham and Women's Hospital, Boston, MA, United States

Abstract

Abstract KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Publisher

American Association for Cancer Research (AACR)

Link

https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-24-0177/3472224/cd-24-0177.pdf

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