Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer
- Creators
-
Mohanty, Atish
- Nam, Arin
- Srivastava, Saumya
-
Jones, Jeff
-
Lomenick, Brett
-
Singhal, Sharad S.
- Guo, Linlin
-
Cho, Hyejin
- Li, Aimin
- Behal, Amita
-
Mirzapoiazova, Tamara
-
Massarelli, Erminia
-
Koczywas, Marianna
-
Arvanitis, Leonidas D.
-
Walser, Tonya
-
Villaflor, Victoria
-
Hamilton, Stanley
-
Mambetsariev, Isa
-
Sattler, Martin
-
Nasser, Mohd W.
-
Jain, Maneesh
-
Batra, Surinder K.
-
Soldi, Raffaella
- Sharma, Sunil
-
Fakih, Marwan
-
Mohanty, Saswat Kumar
-
Mainan, Avijit
-
Wu, Xiwei
- Chen, Yihong
- He, Yanan
-
Chou, Tsui-Fen1
-
Roy, Susmita
-
Orban, John
- Kulkarni, Prakash
-
Salgia, Ravi
-
1.
California Institute of Technology
Abstract
Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin β4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/β-catenin signaling pathway. Thus, silencing both ITGB4 and β-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and β-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.
Copyright and License
© 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
Funding
This work was supported, in part, by NIH grants R01CA218545 (to R.Sa.), R01CA247471 (to R.Sa.), and R01GM141290 (to J.O.). S.R. acknowledges support from the Department of Biotechnology (DBT) (grant no. BT/12/IYBA/2019/12) and Science and Engineering Research Board (SERB), Department of Science and Technology (DST), and the Government of India (grant no. SRG/2020/001295). The cartoons were made using BioRender.com. S.Si. acknowledges support from Department of Defense (W81XWH-22-1-0331). E.M. acknowledges support from Department of Defense (W81XWH-22-1-0450).
Contributions
Conceptualization: A.M., P.K., and R.Sa. Methodology: A.M., A.N., S.Sr., L.G., S.S.S., H.C., X.W., A.L., J.J., B.L., R.So., S.K.M., A.M., Y.C., and Y.H. Investigation: A.M., A.N., S.Sr., S.S.S., and L.G. Visualization: A.M., P.K., R.S., T.-F.C., J.O., and S.R. Supervision: R.Sa., E.M., J.O., T.-F.C., S.R., and X.W. Writing—original draft: A.M., A.N., and P.K. Writing—review and editing: A.M. A.N., S.Sr., J.J., B.L., S.S.S., L.G., H.C., A.L., A.B., T.M., E.M., M.K., L.D.A., T.W., V.V., S.H., I.M., M.S., M.W.N., M.J., S.K.B., R.So., S.Sh., M.F., S.K.M., A.M., X.W., Y.C., Y.H., T.-F.C., S.R., J.O., P.K., and R.Sa.
Data Availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The RNA sequencing data discussed in this publication have been deposited in NCBI's GEO and are accessible via GEO series accession number GSE192619. The DNA sequencing data have been submitted to the SRA database with the accession number PRJNA792406 (www.ncbi.nlm.nih.gov/sra/PRJNA792406).
Conflict of Interest
EC 20-029 is pending as U.S. Patent Application no. 18/017,982 and lists R.Sa., A.M., and P.K. as co-inventors. It was filed on 25 January 2023, is the national stage application corresponding to PCT/US2021/044711, and claims priority to U.S. Provisional Application no. 63/062,628, filed on 7 August 2020. The application is owned by City of Hope, and City of Hope is the applicant. S.Sh. and R.So. have equity in Iterion Therpaeutics that is developing BC 2059. The other authors declare that they have no competing interests.
Files
Additional details
- PMCID
- PMC10575592
- National Institutes of Health
- R01CA218545
- National Institutes of Health
- R01CA247471
- National Institutes of Health
- R01GM141290
- Department of Biotechnology
- BT/12/IYBA/2019/12
- Science and Engineering Research Board
- SRG/2020/001295
- United States Department of Defense
- W81XWH-22-1-0331
- United States Department of Defense
- W81XWH-22-1-0450
- Caltech groups
- Division of Biology and Biological Engineering