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871 Combining KRASG12C(ON) inhibitor with SHP2 and/or immune checkpoint blockade to overcome adaptive resistance and enhance anti-tumour immunity in lung cancer
  1. Panayiotis Anastasiou,
  2. Christopher Moore,
  3. Sareena Rana,
  4. Jesse Boumelha,
  5. Mona Tomaschko,
  6. Miriam Molina-Arcas and
  7. Julian Downward
  1. The Francis Crick Institute, London, UK
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background The approval of mutant-specific KRASG12C inhibitors (G12Ci) has changed the clinical practice for lung cancer patients harbouring KRASG12C mutations. However, responses to G12Ci are short-lived as a result of rapid resistance development.1 2 Combinations with immune checkpoint blockade (ICB), such as anti-PD-1/CTLA-4, which generate long term responses in non-small cell lung cancer patients (NSCLC) present an opportunity for combination with G12Ci as they could potentially enhance the anti-tumour immune responses induced by KRAS inhibition. Recent evidence suggests that these combinations would only be effective in inflamed tumours underlining the necessity for development of further combinatorial approaches to sensitise even immune exclusive/cold tumours.3

Methods In this study we use a novel, covalent tri-complex KRASG12C(ON) inhibitor, RM-029, which targets KRASG12C in the active state in combination with the SHP2 inhibitor RMC-4550 (both preclinical tool compounds), and studied their in vivo anti-tumor activity on transplantable KRAS-mutant lung cancer mouse models of varying immunogenicities. Furthermore, immunoblotting, qPCR and multiplex Flow Cytometry were performed to study both the intrinsic effects and the effects on the tumour microenvironment (TME) of these combinations.

Results In vitro, RM-029 exhibited higher potency for inhibition of cell viability than the KRASG12C(OFF) inhibitor MRTX849 in both human and murine NSCLC cell lines. However, treatment with a KRASG12C(ON) inhibitor RM-029 still resulted in RAS pathway reactivation. Addition of RMC-4550 blocked RAS pathway, induced apoptosis and activation of interferon pathway. In an inflamed, anti-PD-1 sensitive mouse model of NSCLC, KRASG12C(ON) and SHP2 inhibitors alone and in combination profoundly remodel the TME to drive durable responses by suppressing tumour relapse and inducing development of immune memory. However, tumour rejections are driven through the combination of G12Ci and anti-PD-1 immunotherapy. In contrast, combined KRAS and SHP2 inhibition is essential for sensitizing an anti-PD-1 resistant, immune exclusive/cold mouse model of NSCLC to ICB and generate tumour rejection. This is accompanied by significant TME reorganization, including depletion of immunosuppressive innate immune cells and recruitment and activation of T and NK cells.

Conclusions Overall, our preclinical results demonstrate the potential of the combination of KRASG12C(ON) inhibitors with SHP2 inhibitors and/or immune checkpoint blockade not only by targeting KRAS-driven proliferation in tumour cells but by stimulating anti-tumour immunity.

Acknowledgements Compounds and funding were kindly provided by Revolutions Medicines (Redwood City, CA).


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  2. Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, Kim D, Li C, de Stanchina E, Mazutis L, Risso D, Lito P. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020 Jan;577(7790):421–425. doi: 10.1038/s41586-019-1884-x. Epub 2020 Jan 8. PMID: 31915379; PMCID: PMC7308074.

  3. Mugarza E, van Maldegem F, Boumelha J, Moore C, Rana S, Llorian Sopena M, East P, Ambler R, Anastasiou P, Romero-Clavijo P, Valand K, Cole M, Molina-Arcas M, Downward J. Therapeutic KRASG12Cinhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci Adv. 2022 Jul 22;8(29):eabm8780. doi: 10.1126/sciadv.abm8780. Epub 2022 Jul 20. PMID: 35857848; PMCID: PMC9299537.

Ethics Approval All studies were performed under a UK Home Office-approved project license and in accordance with institutional welfare guidelines.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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