Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer
Abstract Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59588-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849729063732641792 |
|---|---|
| author | Xueping Qu Habib Hamidi Radia M. Johnson Ethan S. Sokol Eva Lin Cathy Eng Tae Won Kim Johanna Bendell Smruthy Sivakumar Benjamin Kaplan Felipe de Sousa e Melo Andrew Mancini Matthew Wongchenko Yi Shi David Shames Yibing Yan Fortunato Ciardiello Carlos Bais |
| author_facet | Xueping Qu Habib Hamidi Radia M. Johnson Ethan S. Sokol Eva Lin Cathy Eng Tae Won Kim Johanna Bendell Smruthy Sivakumar Benjamin Kaplan Felipe de Sousa e Melo Andrew Mancini Matthew Wongchenko Yi Shi David Shames Yibing Yan Fortunato Ciardiello Carlos Bais |
| author_sort | Xueping Qu |
| collection | DOAJ |
| description | Abstract Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for 8q gains in anti-EGFR treated patients, potentially linked to MYC amplification, a finding further supported by baseline expression analysis. This work adds to the evidence supporting broader evaluation of EGFR and pan-KRAS inhibitor combinations in CRC patients. It also underscores the utility of EGFR ligands as anti-EGFR efficacy biomarkers and provides a rationale for developing ligand blockers to complement and/or improve conventional anti-EGFR therapies in CRC. |
| format | Article |
| id | doaj-art-99c3444279284575bbfdef9db628dc0e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-99c3444279284575bbfdef9db628dc0e2025-08-20T03:09:20ZengNature PortfolioNature Communications2041-17232025-05-0116111510.1038/s41467-025-59588-3Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancerXueping Qu0Habib Hamidi1Radia M. Johnson2Ethan S. Sokol3Eva Lin4Cathy Eng5Tae Won Kim6Johanna Bendell7Smruthy Sivakumar8Benjamin Kaplan9Felipe de Sousa e Melo10Andrew Mancini11Matthew Wongchenko12Yi Shi13David Shames14Yibing Yan15Fortunato Ciardiello16Carlos Bais17Genentech, IncGenentech, IncGenentech, IncFoundation Medicine, IncGenentech, IncMD Anderson Cancer CenterAsan Medical Center, University of UlsanSarah Cannon Research Institute/Tennessee OncologyFoundation Medicine, IncFoundation Medicine, IncGenentech, IncGenentech, IncGenentech, IncGenentech, IncGenentech, IncGenentech, IncUniversità degli Studi della Campania Luigi VanvitelliGenentech, IncAbstract Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for 8q gains in anti-EGFR treated patients, potentially linked to MYC amplification, a finding further supported by baseline expression analysis. This work adds to the evidence supporting broader evaluation of EGFR and pan-KRAS inhibitor combinations in CRC patients. It also underscores the utility of EGFR ligands as anti-EGFR efficacy biomarkers and provides a rationale for developing ligand blockers to complement and/or improve conventional anti-EGFR therapies in CRC.https://doi.org/10.1038/s41467-025-59588-3 |
| spellingShingle | Xueping Qu Habib Hamidi Radia M. Johnson Ethan S. Sokol Eva Lin Cathy Eng Tae Won Kim Johanna Bendell Smruthy Sivakumar Benjamin Kaplan Felipe de Sousa e Melo Andrew Mancini Matthew Wongchenko Yi Shi David Shames Yibing Yan Fortunato Ciardiello Carlos Bais Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer Nature Communications |
| title | Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer |
| title_full | Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer |
| title_fullStr | Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer |
| title_full_unstemmed | Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer |
| title_short | Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer |
| title_sort | ligand activated egfr mapk signaling but not pi3k are key resistance mechanisms to egfr therapy in colorectal cancer |
| url | https://doi.org/10.1038/s41467-025-59588-3 |
| work_keys_str_mv | AT xuepingqu ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT habibhamidi ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT radiamjohnson ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT ethanssokol ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT evalin ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT cathyeng ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT taewonkim ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT johannabendell ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT smruthysivakumar ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT benjaminkaplan ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT felipedesousaemelo ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT andrewmancini ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT matthewwongchenko ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT yishi ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT davidshames ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT yibingyan ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT fortunatociardiello ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer AT carlosbais ligandactivatedegfrmapksignalingbutnotpi3karekeyresistancemechanismstoegfrtherapyincolorectalcancer |