KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas.
Proc Natl Acad Sci U S A
; 120(29): e2303740120, 2023 07 18.
Article
in En
| MEDLINE
| ID: mdl-37428914
ABSTRACT
Defining reliable surrogate markers and overcoming drug resistance are the most challenging issues for improving therapeutic outcomes of antiangiogenic drugs (AADs) in cancer patients. At the time of this writing, no biomarkers are clinically available to predict AAD therapeutic benefits and drug resistance. Here, we uncovered a unique mechanism of AAD resistance in epithelial carcinomas with KRAS mutations that targeted angiopoietin 2 (ANG2) to circumvent antivascular endothelial growth factor (anti-VEGF) responses. Mechanistically, KRAS mutations up-regulated the FOXC2 transcription factor that directly elevated ANG2 expression at the transcriptional level. ANG2 bestowed anti-VEGF resistance as an alternative pathway to augment VEGF-independent tumor angiogenesis. Most colorectal and pancreatic cancers with KRAS mutations were intrinsically resistant to monotherapies of anti-VEGF or anti-ANG2 drugs. However, combination therapy with anti-VEGF and anti-ANG2 drugs produced synergistic and potent anticancer effects in KRAS-mutated cancers. Together, these data demonstrate that KRAS mutations in tumors serve as a predictive marker for anti-VEGF resistance and are susceptible to combination therapy with anti-VEGF and anti-ANG2 drugs.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma
/
Endothelial Growth Factors
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2023
Document type:
Article
Affiliation country:
Sweden