Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling
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Abstract
Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development. Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined. Results: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody. Conclusions: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.
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TNO155 has demonstrated efficacy when combined with KRAS G12C inhibitors in various preclinical models.
“TNO155, a small-molecular SHP2 inhibitor, has demonstrated efficacy when combined with KRAS G12C inhibitors in various preclinical models [72, 89, 90].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [89]
TNO-155 is an allosteric inhibitor of SHP2 with excellent preclinical antitumor activity and pharmacokinetic data: water solubility 0.736 mM, log P = 1.6, lipophilic efficiency >6, no hERG inhibition (IC50 > 30 μM), no phototoxicity.
“TNO-155 is an allosteric inhibitor of SHP2 that possesses excellent preclinical antitumor activity and pharmacokinetic data: good water solubility (0.736 mM), moderate lipophilic activity (log P = 1.6), high lipophilic efficiency (>6), no hERG inhibition (IC50 > 30 μM) and no phototoxicity.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [273]
Cancers lose sensitivity to KRASG12Ci and re-establish RAS-MAPK signaling through multiple mechanisms, including increased activation of mutant or WT RAS and/or gain of upstream/downstream bypass events.
“Preclinical and clinical studies, however, have demonstrated that cancers lose sensitivity to KRASG12Ci and re-establish RAS-MAPK signaling through multiple mechanisms, including increased activation of mutant or wild-type (WT) RAS and/or gain of upstream/downstream bypass events1,7,9,10,13,14.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [13]
KRASG12Ci plus SHP2i or EGFRi combination approaches are being clinically tested, with evidence of improved clinical response.
“Accordingly, KRASG12Ci plus SHP2 inhibitor (SHP2i; for example TNO155) or EGFR antagonist (EGFRi; for example cetuximab18) combination approaches are now being clinically tested13,16,19,20, with evidence of improved clinical response20–22.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [13]
Co-targeting upstream regulators may block pathway feedback activation and shift both mutant and WT RAS to the GDP-bound state, enhancing downregulation of RAS-MAPK signaling by KRASG12Ci.
“Mechanistically, this approach may block pathway feedback activation and shift both mutant and WT RAS to the GDP-bound state, thus enhancing downregulation of RAS-MAPK pathway signaling by KRASG12Ci (refs. 13,16).”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [13]
Combination approaches that co-target regulators upstream of KRAS, including RTKs and SHP2, improve KRASG12Ci response in preclinical models.
“Combination approaches that co-target regulators upstream of KRAS, including receptor tyrosine kinases (RTKs) and SHP2, improve KRASG12Ci response in preclinical models13,15–17.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [13]
Although combination approaches induced enhanced antiproliferative effects, a moderate rebound of MAPK pathway activity was observed in all models by 48 h after treatment.
“Although combination approaches induced enhanced antiproliferative effects, a moderate rebound of MAPK pathway activity, which might be associated with adaptive resistance to KRASG12C targeted therapy13,16, was observed in all models by 48 h after treatment.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [13]
In the remaining patients, no genomic mechanisms of resistance could be identified, suggesting that non-genetic alterations could be involved.
“In the remaining patients, no genomic mechanisms of resistance could be identified13,16,17,47, suggesting that non-genetic alterations could be involved.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [13]
In heterozygous KRAS mutant tumor cells, RAS signaling can be supplemented and cross-regulated by RTK-WT RAS signaling.
“In heterozygous KRAS mutant tumor cells, RAS signaling can be supplemented and cross-regulated by RTK-WT RAS signaling.”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [43]
Preclinical data show synergistic antiproliferative effects and enhanced antitumor efficacy for SHP2 inhibitor/KRASG12C inhibitor and SOS1 inhibitor/KRASG12C inhibitor combinations.
“Preclinical data has demonstrated synergistic antiproliferative effects and enhanced antitumor efficacy for both the SHP2 inhibitor/KRASG12C inhibitor combination (43) and the SOS1 inhibitor/KRASG12C inhibitor combination (44, 45).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [43]
Combining a mutant-specific KRAS inhibitor with a SHP2 or SOS1 inhibitor could block both mutant KRAS and wild-type RAS signaling.
“A combination of a mutant specific KRAS inhibitor with either a SHP2 inhibitor or a SOS1 inhibitor could effectively block mutant KRAS and wild-type RAS signaling (12, 43, 45, 46).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [43]
TNO155 inhibits MAPK signaling and enhances the efficacy of KRAS G12C inhibitors against KRAS G12C lung and colorectal cancers.
“The SHP2 inhibitor developed by Novartis, TNO155, inhibits MAPK signaling and enhances the efficacy of KRAS (G12C) inhibitors against KRAS (G12C) lung and colorectal cancers.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [49]
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Self-citationOncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Tang, D., Kroemer, G., & Kang, R. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01422-7 · Cited by 80 · see citing works
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Targeted Degradation of the Oncogenic Phosphatase SHP2
Vemulapalli, V., Donovan, K. A., Seegar, T. C. M., Rogers, J. M., Bae, M., Lumpkin, R. J., Cao, R., Henke, M. T., Ray, S. S., Fischer, E. S., et al. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00377 · Cited by 43 · see citing works
The Next Generation of KRAS Targeting: Reasons for Excitement and Concern
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“TNO155, a small ‐ molecular SHP2 inhibitor, has demonstrated efficacy when combined with KRAS G12C inhibitors in various preclinical models [74, 92, 93].”
- Authors
- Liu, C., Lu, H., Wang, H., Loo, A., Zhang, X., Yang, G., Kowal, C., Delach, S., Wang, Y., Goldoni, S., Hastings, W. D., Wong, K., Gao, H., Meyer, M. J., Moody, S. E., LaMarche, M. J., Engelman, J. A., Williams, J. A., Hammerman, P. S., Abrams, T. J., Mohseni, M., Caponigro, G., & Hao, H.-X.
- Affiliations
- 1Oncology Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
- Novartis Institutes for BioMedical Research (CH)
- 3Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
- Corresponding author
- Caponigro, Giordano
- Hao, Huai-Xiang
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-01-01
- Volume
- 27
- Issue
- 1
- Pages
- 342-354
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W3092240262
- Semantic Scholar
- 1c2add0689b38e1850ae8d3b4ba2a16a4fb2b71a
- Cited by
- 167
- References
- 52
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 35 · 2023: 37 · 2022: 27 · 2021: 19
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- TNO155, SHP2 inhibitors, receptor tyrosine kinase signaling, drug combination therapy, EGFR-mutant lung cancer, KRAS G12C, CSF1R, tumor-associated macrophages, anti-PD-1, tumor microenvironment
- MeSH terms
- Immune Checkpoint Inhibitors, Tumor-Associated Macrophages, Allosteric Regulation, Animals, Antineoplastic Combined Chemotherapy Protocols, Drug Synergism, Female, Humans, Mutation, Neoplasms, Proto-Oncogene Proteins p21(ras), Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Programmed Cell Death 1 Receptor, ErbB Receptors
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