Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R
Open accessAbstract
Although several KRas G12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRas G12C inhibitors. To explore the mechanism rendering acquired resistance to KRas G12C inhibitors, we established a series of KRAS G12C-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 KRAS G12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRAS G12C-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 KRas G12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRas G12C inhibitors for therapy of KRAS G12C-mutant cancers in future clinical trials.
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Increased levels of phospho-EGFR and phospho-IGFR were detected in sotorasib-resistant KRAS G12C NSCLC, PDAC, and CRC cell lines.
“Increased levels of phospho-EGFR and phospho-IGFR were detected in sotorasib-resistant KRAS G12C NSCLC, PDAC, and CRC cell lines [76].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [76]
The ‘Activation of RTKs rendered KRAS G12C-mutant cells resistant to AMG510’ section reports increased phosphorylation of EGFR and IGF1R in resistant NSCLC cells. It reports elevated phospho-EGFR in the resistant PDAC line MIA PaCa-2, but phospho-IGF1R in the resistant CRC line SW837. The claim does not preserve that distinction and can imply that both increased in all three cancer types. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCombining sotorasib with the PI3Kα inhibitor CYH33 was synergistic against KRAS G12C cancer cells in vitro and in vivo.
“Combining sotorasib with the PI3Kα inhibitor CYH33 was synergistic against KRAS G12C cancer cells in vitro and in vivo [76].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [76]
RTK activation is responsible for elevated downstream signaling.
“Additionally, RTK activation is responsible for elevated downstream signaling [73, 76].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [76]
PI3K integrates signals from multiple RTKs, and the activity of PI3K/AKT was negatively correlated with the sensitivity to KRAS G12C inhibitors.
“Analysis of sotorasib-resistant KRAS G12C cancer cells showed that PI3K integrates signals from multiple RTKs, and the activity of PI3K/AKT was negatively correlated with the sensitivity to KRAS G12C inhibitors [76].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [76]
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Cited by
Sorted by citations
Differential Response and Resistance to KRAS-Targeted Therapy
Liu, Z., Lenz, H., Yu, J., & Zhang, L. (2025) · Molecular Carcinogenesis · doi:10.1002/mc.23908 · Cited by 7 · see citing works
“Increased levels of phospho ‐ EGFR and phospho ‐ IGFR were detected in sotorasib ‐ resistant KRAS G12C NSCLC, PDAC, and CRC cell lines [78].”
Influential
- Authors
- Qi, W.-L., Li, H.-Y., Wang, Y., Xu, L., Deng, J.-T., Zhang, X., Wang, Y.-X., & Meng, L.-H.
- Affiliations
- Nanchang University (CN)
- Chinese Academy of Sciences (CN)
- Nanjing University of Chinese Medicine (CN)
- Venue
- Acta Pharmacologica Sinica
- Published
- 2022-11-21
- Volume
- 44
- Issue
- 5
- Pages
- 1083-1094
- ISSN
- 0253-9756 (ISSN-L)
- 1671-4083
- 1745-7254
- PMC
- PMC10104814
- OpenAlex
- W4309656491
- Cited by
- 19
- References
- 18
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 1 · 2022: 1
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Acta Pharmacologica Sinica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (82173832, 82104199, 81973345)
- Science and Technology Commission of Shanghai Municipality (22ZR1474400)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C inhibitors, acquired drug resistance, PI3Kα inhibitor, sotorasib, EGFR, IGF-1 receptor, receptor tyrosine kinase activation, Akt signaling, MAPK signaling, combination therapy
- MeSH terms
- Immune Checkpoint Inhibitors, Mutation, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Receptor, IGF Type 1, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, ErbB Receptors
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