A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer

A novel Drosophila-based approach resulted in a significant response by a patient with KRAS-mutant colorectal cancer. Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

[1]  J. Meyerhardt,et al.  NCCN Guidelines Insights: Colon Cancer, Version 2.2018. , 2018, Journal of the National Comprehensive Cancer Network : JNCCN.

[2]  D. Nielsen,et al.  Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: A systematic review. , 2018, Cancer treatment reviews.

[3]  M. Mahajan,et al.  Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma , 2017, Cold Spring Harbor molecular case studies.

[4]  R. Mountford,et al.  Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer , 2017, British Journal of Cancer.

[5]  F. Ciardiello,et al.  Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK. , 2017, Cancer treatment reviews.

[6]  O. Sansom,et al.  Functional exploration of colorectal cancer genomes using Drosophila , 2016, Nature Communications.

[7]  M. Fakih,et al.  RAS and BRAF in metastatic colorectal cancer management. , 2016, Journal of gastrointestinal oncology.

[8]  Shung-Haur Yang,et al.  Mutation spectra of RAS gene family in colorectal cancer. , 2016, American journal of surgery.

[9]  Benjamin S. Glicksberg,et al.  Development and clinical application of an integrative genomic approach to personalized cancer therapy , 2016, Genome Medicine.

[10]  L. Kwong,et al.  Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models , 2016, Oncotarget.

[11]  E. Boerwinkle,et al.  dbNSFP v3.0: A One‐Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice‐Site SNVs , 2016, Human mutation.

[12]  Joon-Oh Park,et al.  The impact of KRAS mutations on prognosis in surgically resected colorectal cancer patients with liver and lung metastases: a retrospective analysis , 2016, BMC Cancer.

[13]  Ying Cheng,et al.  Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. , 2015, The Lancet. Oncology.

[14]  Marc Peeters,et al.  Randomized trial of TAS-102 for refractory metastatic colorectal cancer. , 2015, The New England journal of medicine.

[15]  C. Qu,et al.  Value of bevacizumab in treatment of colorectal cancer: A meta-analysis. , 2015, World journal of gastroenterology.

[16]  T. Yuen,et al.  Bisphosphonates inactivate human EGFRs to exert antitumor actions , 2014, Proceedings of the National Academy of Sciences.

[17]  N. Perrimon,et al.  Combining genetic perturbations and proteomics to examine kinase-phosphatase networks in Drosophila embryos. , 2014, Developmental cell.

[18]  A. Iafrate,et al.  Mutational analysis and clinical correlation of metastatic colorectal cancer , 2014, Cancer.

[19]  D. Esposito,et al.  Dragging ras back in the ring. , 2014, Cancer cell.

[20]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[21]  S. An.  Faculty Opinions recommendation of K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. , 2014 .

[22]  Taebo Sim,et al.  Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. , 2014, Angewandte Chemie.

[23]  M. Choti,et al.  Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases , 2013, Cancer.

[24]  Kevan M. Shokat,et al.  K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions , 2013, Nature.

[25]  Y. Ba,et al.  Bevacizumab plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as the second-line therapy for patients with metastatic colorectal cancer, a multicenter study , 2013, Medical Oncology.

[26]  I. Nagtegaal,et al.  KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy , 2013, International journal of cancer.

[27]  P. Bastiaens,et al.  Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling , 2013, Nature.

[28]  Jeffrey J Meyer,et al.  Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012. (5) , 2013 .

[29]  Kazuhiro Yoshida,et al.  Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability , 2013, Journal of hepato-biliary-pancreatic sciences.

[30]  D. Sargent,et al.  Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial , 2013, The Lancet.

[31]  K. Flaherty,et al.  Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. , 2012, The Lancet. Oncology.

[32]  K. Flaherty,et al.  Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. , 2012, The Lancet. Oncology.

[33]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[34]  Enzo Medico,et al.  Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer , 2012, Nature.

[35]  J. Grande,et al.  VEGF Inhibition, Hypertension, and Renal Toxicity , 2012, Current Oncology Reports.

[36]  R. Eastell,et al.  Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate—Danish National Register Based Cohort Study , 2012, Osteoporosis International.

[37]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[38]  D. Zopf,et al.  Regorafenib (BAY 73‐4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity , 2011, International journal of cancer.

[39]  Norbert Perrimon,et al.  A genome-scale shRNA resource for transgenic RNAi in Drosophila , 2011, Nature Methods.

[40]  S. Gruber,et al.  Use of bisphosphonates and reduced risk of colorectal cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  S. Nelson,et al.  Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation , 2010, Nature.

[42]  J. Hornberg,et al.  Abstract B4: Regorafenib: a new oral multikinase inhibitor of angiogenic, stromal and oncogenic (receptor tyrosine) kinases with potent preclinical antitumor activity , 2009 .

[43]  Mikhail Teverovskiy,et al.  A systems pathology model for predicting overall survival in patients with refractory, advanced non-small-cell lung cancer treated with gefitinib. , 2009, European journal of cancer.

[44]  L. Mazzucchelli,et al.  Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  W. Scheithauer,et al.  Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  F. Schmidt.  Meta-Analysis , 2008 .

[47]  H. Izzedine,et al.  Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. , 2007, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[48]  Michalis V. Karamouzis,et al.  Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets , 2007, Nature Reviews Drug Discovery.

[49]  P. Catalano,et al.  Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  Silvia Benvenuti,et al.  Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. , 2007, Cancer research.

[51]  R. Maeda,et al.  An optimized transgenesis system for Drosophila using germ-line-specific φC31 integrases , 2007, Proceedings of the National Academy of Sciences.

[52]  Jean-Philippe Vert,et al.  An accurate and interpretable model for siRNA efficacy prediction , 2006, BMC Bioinformatics.

[53]  A. Lièvre,et al.  KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. , 2006, Cancer research.

[54]  D. Guay.  Ibandronate: a new oral bisphosphonate for postmenopausal osteoporosis. , 2005, The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists.

[55]  M. Valerio,et al.  Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  H. Mo,et al.  Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention , 2004, Experimental biology and medicine.

[57]  M. Minden,et al.  HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis , 2002, Leukemia.

[58]  이석호,et al.  Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study , 2001, British Journal of Cancer.

[59]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[60]  M. F. Parry,et al.  A Retrospective Analysis , 1990 .