Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R

Acta Pharmacologica Sinica volume 44, pages 1083–1094 (2023)Cite this article

Abstract

Although several KRasG12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRasG12C inhibitors. To explore the mechanism rendering acquired resistance to KRasG12C inhibitors, we established a series of KRASG12C-mutant cells with acquired resistance to AMG510. We found that differential activation of receptor tyrosine kinases (RTKs) especially EGFR or IGF1R rendered resistance to AMG510 in different cellular contexts by maintaining the activation of MAPK and PI3K signaling. Simultaneous inhibition of EGFR and IGF1R restored sensitivity to AMG510 in resistant cells. PI3K integrates signals from multiple RTKs and the level of phosphorylated AKT was revealed to negatively correlate with the anti-proliferative activity of AMG510 in KRASG12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRASG12C-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRasG12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRasG12C inhibitors for therapy of KRASG12C-mutant cancers in future clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: AMG510 displayed variable anti-proliferative efficacy in KRASG12C-mutant cells.
Fig. 2: KrasG12C-mutant cells developed acquired resistance after continuous exposure to AMG510.
Fig. 3: Activation of RTKs rendered KRASG12C-mutant cells resistant to AMG510.
Fig. 4: Blockade of RTKs signaling potentiated the activity of AMG510 in resistant cells.
Fig. 5: Combination of the PI3Kα inhibitor with AMG510 synergistically inhibited proliferation of KRASG12C-mutant cells.
Fig. 6: Combination of CYH33 with AMG510 synergistically inhibited the growth of xenografts derived from KRASG12C-mutant cells.

Similar content being viewed by others

References

  1. Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. Expanding the reach of precision oncology by drugging All KRAS mutants. Cancer Discov. 2022;12:924–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Khan I, Rhett JM, O’Bryan JP. Therapeutic targeting of RAS: New hope for drugging the “undruggable”. Biochim Biophys Acta Mol Cell Res. 2020;1867:118570.

    Article  CAS  PubMed  Google Scholar 

  3. Schaber MD, Garsky VM, Boylan D, Hill WS, Scolnick EM, Marshall MS, et al. Ras interaction with the gtpase-activating protein (Gap). Proteins. 1989;6:306–15.

    Article  CAS  PubMed  Google Scholar 

  4. Lu S, Jang H, Gu S, Zhang J, Nussinov R. Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view. Chem Soc Rev. 2016;45:4929–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Banno K, Yanokura M, Iida M, Masuda K, Aoki D. Carcinogenic mechanisms of endometrial cancer: involvement of genetics and epigenetics. J Obstet Gynaecol Res. 2014;40:1957–67.

    Article  CAS  PubMed  Google Scholar 

  6. Siqi Li ABCMC. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer. 2018;18:767–77.

    Article  PubMed  Google Scholar 

  7. Balmain A, Pragnell IB. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature. 1983;303:72–4.

    Article  CAS  PubMed  Google Scholar 

  8. Sukumar S, Notario V, Martin-Zanca D, Barbacid M. Induction of mammary carcinomas in rats by nitrosomethyl-urea involves the malignant activation of the H-ras-1 locus by single point mutations. Nature. 1983;306:658–61.

    Article  CAS  PubMed  Google Scholar 

  9. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13:828–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217–23.

    Article  CAS  PubMed  Google Scholar 

  11. Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, et al. Targeting KRAS mutant cancers with a covalent G12C-Specific inhibitor. Cell. 2018;172:578–89.e17.

    Article  CAS  PubMed  Google Scholar 

  12. Johnson ML, Ou SHI, Barve M, Rybkin II, Papadopoulos KP, Leal TA, et al. Activity and safety of Adagrasib (MRTX849) in patients with colorectal cancer (CRC) and other solid tumors harboring a KRAS G12C mutation. Eur J Cancer. 2020;138:S2.

    Article  Google Scholar 

  13. Jänne PA, Rybkin II, Spira AI, Riely GJ, Papadopoulos KP, Sabari JK, et al. Activity and safety of Adagrasib (MRTX849) in advanced/ metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur J Cancer. 2020;138:S1–2.

    Article  Google Scholar 

  14. Patricelli MP, Janes MR, Li L-S, Hansen R, Peters U, Kessler LV, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 2016;6:316–29.

    Article  CAS  PubMed  Google Scholar 

  15. Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351:604–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li H-y, Qi W-l, Wang Y-x, Meng L-h. Covalent inhibitor targets KRasG12C: a new paradigm for drugging the undruggable and challenges ahead. Genes Dis. 2021; https://doi.org/10.1016/j.gendis.2021.08.011.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, et al. Discovery of a covalent inhibitor of KRAS(G12C) (AMG 510) for the treatment of solid tumors. J Med Chem. 2020;63:52–65.

    Article  CAS  PubMed  Google Scholar 

  18. Jiao D, Yang S. Overcoming resistance to drugs targeting KRAS mutation. Innovation. 2020;1:100035.

    PubMed  PubMed Central  Google Scholar 

  19. Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, et al. FDA Approval Summary: Sotorasib for KRAS G12C-mutated metastatic NSCLC. Clin Cancer Res. 2022;28:1482–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ou SI, Janne PA, Leal TA, Rybkin, II, Sabari JK, Barve MA, et al. First-in-human phase I/IB dose-finding study of Adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40:JCO2102752.

  21. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25.

    Article  CAS  PubMed  Google Scholar 

  22. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus Crizotinib in Untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829–38.

    Article  CAS  PubMed  Google Scholar 

  23. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition. Clin Cancer Res. 2020;26:1633–43.

    Article  CAS  PubMed  Google Scholar 

  24. Amodio V, Yaeger R, Arcella P, Cancelliere C, Lamba S, Lorenzato A, et al. EGFR blockade reverts resistance to KRAS(G12C) inhibition in colorectal cancer. Cancer Discov. 2020;10:1129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Misale S, Fatherree JP, Cortez E, Li CD, Bilton S, Timonina D, et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res. 2019;25:796–807.

    Article  CAS  PubMed  Google Scholar 

  26. Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020;577:421–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med. 2021;384:2382–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu XL, Wang BB, Wang Y, Wang YX, Yang CH, Tan C, et al. Unbiased screening reveals that blocking exportin 1 overcomes resistance to PI3Kalpha inhibition in breast cancer. Signal Transduct Target Ther. 2019;4:49.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Li X, Tong LJ, Ding J, Meng LH. Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer. Cancer Lett. 2014;342:159–66.

    Article  CAS  PubMed  Google Scholar 

  30. Shi JJ, Chen SM, Guo CL, Li YX, Ding J, Meng LH. The mTOR inhibitor AZD8055 overcomes tamoxifen resistance in breast cancer cells by down-regulating HSPB8. Acta Pharmacol Sin. 2018;39:1338–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tang J, Wennerberg K, Aittokallio T. What is synergy? The Saariselka agreement revisited. Front Pharmacol. 2015;6:181.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ni D, Li X, He X, Zhang H, Zhang J, Lu S. Drugging K-Ras(G12C) through covalent inhibitors: mission possible? Pharmacol Ther. 2019;202:1–17.

    Article  CAS  PubMed  Google Scholar 

  33. Liu P, Wang Y, Li X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm Sin B. 2019;9:871–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Rodenhuis, S. ras and human tumors. Semin Cancer Biol. 1992;3:241–7.

  35. Rubin SM, Sage J, Skotheim JM. Integrating old and new paradigms of G1/S control. Mol Cell. 2020;80:183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P, et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019;11:eaaw7999.

  37. Xiang HY, Wang X, Chen YH, Zhang X, Tan C, Wang Y, et al. Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors. Eur J Med Chem. 2021;209:112913.

    Article  CAS  PubMed  Google Scholar 

  38. Adachi Y, Ito K, Hayashi Y, Kimura R, Tan TZ, Yamaguchi R, et al. Epithelial-to-mesenchymal transition is a cause of both intrinsic and acquired resistance to KRAS G12C inhibitor in KRAS G12C-mutant non-small cell lung cancer. Clin Cancer Res. 2020;26:5962–73.

    Article  CAS  PubMed  Google Scholar 

  39. Suzuki S, Yonesaka K, Teramura T, Takehara T, Kato R, Sakai H, et al. KRAS inhibitor resistance in MET-amplified KRAS (G12C) non-small cell lung cancer induced By RAS- and non-RAS-mediated cell signaling mechanisms. Clin Cancer Res. 2021;27:5697–707.

    Article  CAS  PubMed  Google Scholar 

  40. Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nature. 2018;15:709–20.

    CAS  Google Scholar 

  41. Hallin, J, Engstrom, LD, Hargis, L, Calinisan, A, Aranda, R, Briere, DM. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10:54–71.

  42. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19:533–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res. 2012;18:2316–25.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (82104199, 82173832 and 81973345), the Lingang Laboratory (LG202103-02-03) and Science and Technology Commission of Shanghai Municipality (22ZR1474400).

Author information

Authors and Affiliations

  1. Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China

    Wei-liang Qi, Hui-yu Li, Yi Wang, Lan Xu, Xi Zhang, Yu-xiang Wang & Ling-hua Meng

  2. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China

    Wei-liang Qi, Hui-yu Li & Ling-hua Meng

  3. College of Pharmacy, Nanchang University, No. 461, Bayi Road, Nanchang, 330006, China

    Wei-liang Qi

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Jie-ting Deng & Ling-hua Meng

Authors
  1. Wei-liang Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui-yu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jie-ting Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-xiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ling-hua Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LHM, YXW, and WLQ conceived the study and wrote the manuscript. WLQ carried most of the experiments. HYL, JTD, and XZ performed part of the cell proliferation and Western blotting assay. YW established AMG510-acquired resistance cell lines. LX conducted part of animal experiments. LHM and YXW supervised the study. All authors proofread the manuscript and approved to submit the final manuscript.

Corresponding authors

Correspondence to Yu-xiang Wang or Ling-hua Meng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qi, Wl., Li, Hy., Wang, Y. et al. Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R. Acta Pharmacol Sin 44, 1083–1094 (2023). https://doi.org/10.1038/s41401-022-01015-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-022-01015-0

Keywords

Search

Advanced search

Quick links