title: A set of defined oncogenic mutation alleles seems to better predict the response to cetuximab in CRC patient-derived xenograft than KRAS 12/13 mutations.
abstract: Cetuximab is a standard of care for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) exclusive of those with KRAS mutations at codons 12/13. However, retrospective analysis has recently suggested that KRAS-G13D patients can still benefit, while only a fraction of KRAS wild-type patients can benefit, from the treatment. We set out to test this contradicting issue experimentally in an independent cohort of patient derived xenograft (PDX) diseases. We conducted a mouse clinical trial (MCT) enrolling a random cohort of 27 transcriptome sequenced CRC-PDXs to evaluate cetuximab activity. The treatment responses were analyzed against the KRAS 12/13 mutation alleles, as well as several other well-known oncogenic alleles. If the response is defined by >80% tumor growth inhibition, 8/27 PDXs (~30%) are responders versus 19/27 non-/partial responders (~70%). We found that indeed there are no significantly fewer KRAS-12/13-allele responders (4/8 or 50%) than non-/partial responders (7/19, or 37%). In particular, there are actually no fewer G13D responders (4/8, or 50%) than in non-/partial responders (2/19 or 10.5%) statistically. Furthermore, majority of the non-/partial responders tend to have certain activating oncogenic alleles (one or more of the following common ones: K/N-RAS-G12V/D, -A146T, -Q61H/R, BRAF-V600E, AKT1-L52R and PIK3CA-E545G/K). Our data on an independent cohort support the recent clinical observation, but against the current practiced patient stratification in the cetuximab CRC treatment. Meanwhile, our data seem to suggest that a set of the six-oncogenic alleles may be of better predictive value than the current practiced stratification, justifying a new prospective clinical investigation on an independent cohort for confirmation.
authors.affiliation: Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
authors.affiliation: Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Guo
authors.affiliation: Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Wubin
authors.initials: W
authors.lastname: Qian
authors.affiliation: Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Wery
authors.affiliation: Crown Bioscience, Inc., Santa Clara, CA 95054, USA.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Qi-Xiang
authors.initials: QX
authors.lastname: Li
mesh_terms: D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: KRAS; PDX; biomarker; erbitux; patient stratification