Lasting response by vertical inhibition with cetuximab and trametinib in KRAS-mutated colorectal cancer patient-derived xenografts.
Timm M ReissigSwetlana Ladigan-BaduraAnja SteinbergAbdelouahid MaghnoujTing LiBerlinda VerdoodtSven T LiffersMichael PohlHeiner WoltersChristian TeschendorfRichard ViebahnJakob AdmardNicolas CasadeiAndrea TannapfelWolff SchmiegelStephan A HahnDeepak Ben VangalaPublished in: Molecular oncology (2023)
Although approximately half of all metastatic colorectal cancers (mCRCs) harbor mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumors with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumors were tested. Responses were evaluated according to baseline tumor changes and graded as partial response (PR; ≤-30%), stable disease (SD; between -30% and +20%) or progressive disease (PD; ≥+20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analyzed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance. Molecular analyses revealed that primary and secondary resistance was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumors. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.
Keyphrases
- wild type
- combination therapy
- epidermal growth factor receptor
- tyrosine kinase
- clinical trial
- small cell lung cancer
- end stage renal disease
- advanced non small cell lung cancer
- gene expression
- risk factors
- newly diagnosed
- squamous cell carcinoma
- chronic kidney disease
- multiple sclerosis
- randomized controlled trial
- machine learning
- young adults
- signaling pathway
- peritoneal dialysis
- radiation therapy
- bone marrow
- diabetic rats
- mass spectrometry
- artificial intelligence
- cancer therapy
- high glucose
- double blind
- heat stress