Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 18:633:217984.
doi: 10.1016/j.canlet.2025.217984. Online ahead of print.

Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress

Akash Sabarwal  1 , Marc Machaalani  2 , Laxminarayan Rawat  1 , Johannes Wedel  3 , Saba Tabasum  4 , Yuzuru Sasamoto  5 , Florian Buerger  6 , Josie Ascione  2 , Marc Eid  2 , Karl Semaan  2 , Eddy Saad  2 , Yifan Yang  2 , Dongwon Lee  1 , F Stephen Hodi  4 , Matthew L Freedman  7 , Gwo-Shu Mary Lee  2 , Murugabaskar Balan  1 , Toni K Choueiri  7 , Soumitro Pal  8
Affiliations

Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress

Akash Sabarwal et al. Cancer Lett. .

Abstract

The mechanisms underlying therapeutic resistance to c-Met/receptor tyrosine kinase (RTK) inhibitors in renal cancer remain unexplored. In renal cell carcinoma (RCC) cells, both AXL and c-Met are highly upregulated. Notably, we found that prolonged treatment with the c-Met/RTK inhibitor, cabozantinib (Cabo), a standard treatment for advanced-stage RCC, markedly increased total c-Met levels and promoted renal cancer cell proliferation. This effect was confirmed not only in vitro but also in murine models and renal tumor tissues from Cabo-treated patients. At lower concentrations (1 nM and 10 nM), Cabo treatment failed to inhibit HGF (c-Met ligand)-induced c-Met phosphorylation. Instead, it further enhanced receptor phosphorylation and downstream signaling events for tumor growth. Additionally, Cabo treatment induced AXL-c-Met association and disrupted the physiological degradation of c-Met. However, inhibition or knockout of AXL could significantly overcome therapeutic resistance to c-Met inhibitor(s). It triggered apoptotic cell death through increased oxidative stress and inhibition of the redox-sensitive transcription factor, Nrf2 and its effector molecule, heme oxygenase-1 (HO-1). We also generated Cabo-resistant RCC cells and observed a marked upregulation of both c-Met and AXL in these cells. Epigenomic profiling revealed significant differences between Cabo-resistant and Cabo-sensitive RCC cells. Importantly, inhibition of AXL either using a potent inhibitor, TP-0903, or through genetic silencing resensitized the resistant cells to Cabo-induced cell death. Together, our findings highlight AXL as a key driver of therapeutic resistance to c-Met inhibitors. A combination therapy targeting both c-Met and AXL in renal cancer could be a promising strategy to overcome the acquired resistance to c-Met inhibitors through increased oxidative stress.

Keywords: AXL; HO-1; Nrf2; Oxidative stress; Renal cancer; Therapeutic resistance; c-Met.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: • Dr. Pal reports research support from Exelixis. Dr. Freedman is a co-founder and shareholder of Precede Biosciences. Dr. Choueiri reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria past 5 years, ongoing or not, from: Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work.·Institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA.·Equity: Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium.·Committees: NCCN, GU Steering Committee, ASCO (BOD 6-2024-, ESMO, ACCRU, KidneyCan.·Medical writing and editorial assistance support may have been funded by Communications companies in part.·No speaker’s bureau. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components.• The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royaltiespotentially involved in research around the subject matter.Dr. Hodi reports grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from Novartis, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Bicara, personal fees from Checkpoint Therapeutics, personal fees from Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees from Catalym, personal fees from Immunocore, personal fees from Kairos, personal fees from Rheos, personal fees from Bayer, personal fees from Zumutor, personal fees from Corner Therapeutics, personal fees from Puretech, personal fees from Curis, personal fees from Astra Zeneca, personal fees from Pliant, personal fees from Solu Therapeutics, personal fees from Vir Biotechnology, personal fees from 92Bio, outside the submitted work; In addition, Dr. Hodi has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent THERAPEUTIC PEPTIDES Therapeutic Peptides patent number: 9402905 issued, a patent METHODS OF USING PEMBROLIZUMAB AND TREBANANIB pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 with royalties paid, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, a patent ÚNTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES Publication number: 20170343552 pending, and a patent Antibodies against EDIL3 and methods of use thereof pending.

References

    1. Li M, Li L, Zheng J, Li Z, Li S, Wang K, Chen X, Liquid biopsy at the frontier in renal cell carcinoma: recent analysis of techniques and clinical application, Molecular Cancer, 22 (2023) 37. - PMC - PubMed
    1. Wang Y, Suarez ER, Kastrunes G, de Campos NSP, Abbas R, Pivetta RS, Murugan N, Chalbatani GM, D’Andrea V, Marasco WA, Evolution of cell therapy for renal cell carcinoma, Molecular Cancer, 23 (2024) 8. - PMC - PubMed
    1. Waldman AD, Fritz JM, Lenardo MJ, A guide to cancer immunotherapy: from T cell basic science to clinical practice, Nature Reviews Immunology, 20 (2020) 651–668. - PMC - PubMed
    1. Liu Z-L, Chen H-H, Zheng L-L, Sun L-P, Shi L, Angiogenic signaling pathways and anti-angiogenic therapy for cancer, Signal Transduction and Targeted Therapy, 8 (2023) 198. - PMC - PubMed
    1. Kim JH, Kim BJ, Kim HS, Clinicopathological impacts of high c-Met expression in renal cell carcinoma: a meta-analysis and review, Oncotarget, 8 (2017) 75478–75487. - PMC - PubMed

LinkOut - more resources