The overall focus of the Doebele laboratory is the study of oncogene-targeted therapy in cancer. Initially our lab focused on a particular subtype of oncogenes termed gene fusions such as ALK, ROS1, RET in lung cancer, defining how cancer cells become resistant to oncogene targeted therapies.
Following the discovery of NTRK1 gene fusions in lung cancer and the realization that NTRK1/2/3 fusions occur across nearly tumor types, we pursued a novel idea that some therapies, for example those directed against oncogenes, could be developed using a tumor agnostic approach, an idea that has come to fruition with the FDA approval of larotrectinib for NTRK1/2/3 fusions in any adult or pediatric tumors. Clinical development of TRK inhibitors was supported using human-derived cell line models from our laboratory and supported by our generous patients who donate tissue and fluid samples for research. The CUTO3 (NTRK1 fusion positive) cell line was immensely useful in the rapid development of TRK inhibitors. Our library of cell lines has now grown rapidly and includes the first ever developed EGFR exon 20 insertion cell lines (CUTO14/17/18) that are being used by both academic laboratories and industry collaborators for new drug development in this difficult to treat subset.
Knowing that patient responses to therapy and emergent drug resistance mechanisms vary by patient, and thus one cell line model for each oncogene type cannot be representative, we are also building libraries of human derived cell line models for ALK, ROS1, RET and other oncogene subtypes to better understand interpatient heterogeneity for the development of new therapies.
Utilizing these patient-derived models, we use genetic, proteomic and bioinformatic approaches to elucidate both the sensitivity and cellular resistance to oncogene-targeted therapy. We have applied these approaches to ALK and ROS1+ lung cancer to elucidate novel mechanisms of drug resistance. Although much progress has been made on drugging kinase domain mutations that generate drug resistance, understanding how to detect and treat bypass signaling mechanism is an area of need. Ultimately, our goal is to advance personalized medicine through the identification, analysis, and rational targeting of driver oncogenes in cancer in order to improve the clinical outcomes of patients with this disease by understanding the adaptive mechanisms of cancer cells upon treatment.
Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman D, Heasley LE, Franklin WA, Varella-Garcia M, and Camidge DR. Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-Small Cell Lung Cancer. Clin Cancer Res. 2012 Mar 1;18(5):1472-82. PMCID: PMC3311875.
Davies KD, Mahale S, Astling DP, Aisner DL, Le AT, Hinz TK, Vaishnavi A, Bunn PA, Heasley L, Tan AC, Camidge DR, Varella-Garcia M, Doebele RC. Resistance to ROS1 Inhibition Mediated by EGFR Pathway Activation in Non-Small Cell Lung Cancer. PLoS One. 2013 Dec 13;8(12):e82236. PMCID: PMC3862576.
Cargnelutti M, Corso S, Pergolizzi M, Mévellec L, Aisner DL, Dziadziuszko R, Varella-Garcia M, Comoglio PM, Doebele RC, Vialard J and Giordano S. Activation of RAS family members confers resistance to ROS1 targeting drugs. Oncotarget. 2014 Dec 31. [Epub ahead of print]. PMCID: PMC4467141.
Dziadziuszko R, Le AT, Wrona A, Jassem J, Camidge DR, Varella-Garcia M, Aisner DL, Doebele RC. An activating KIT mutation induces crizotinib resistance in ROS1 positive lung cancer. J Thorac Oncol. 2016 Aug;11(8):1273-81. PMID: 27068398.
Nelson-Taylor SK, Le AT, Yoo M, Schubert L, Mishall KM, Doak A, Varella-Garcia M, Tan AC, and Doebele RC. Resistance to RET-inhibition in RET-rearranged NSCLC is mediated by reactivation of RAS/MAPK signaling. Mol Cancer Ther. 2017 Aug;16(8):1623-1633. PMID: 28500237.
McCoach CE, Blakely CM, Banks KC, Levy BM, Chue B, Raymond VM, Le A, Lee CE, Diaz J, Waqar SN, Purcell WT, Aisner DL, Davies KD, Lanman RB, Shaw AT, Doebele RC. Clinical utility of cell-free DNA for the detection of ALK fusions and genomic mechanisms of ALK inhibitor resistance in non-small cell lung cancer. Clin Cancer Res. 2018 Mar 29. pii: clincanres.2588.2017. doi: 10.1158/1078-0432.CCR-17-2588. [Epub ahead of print]. PMID: 29599410.
McCoach CE, Le AT, McGowan K, Jones K., Schubert L, Doak A, Estrada-Bernal A, Davies KD, Merrick, DT, Bunn PA, Purcell WT, Dziadziuszko R, Varella-Garcia M, Aisner DL, Camidge DR, and Doebele RC. Resistance mechanisms to targeted therapies in ROS1+ and ALK+ non-small cell lung cancer. Clin Cancer Res. 2018 Mar 29. pii: clincanres.2588.2017. doi: 10.1158/1078-0432.CCR-17-2588. [Epub ahead of print]. PMID: 29599410.
Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, Zhu VW, Ahn MJ, Camidge DR, Nguyen J, Zhai D, Deng W, Huang Z, Rogers E, Liu J, Whitten J, Lim JK, Stopatschinskaja S, Hyman DM, Doebele RC, Cui JJ, Shaw AT. Repotrectinib (TPX-0005) is a next generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent front mutations. Cancer Discov. 2018 Aug 9. pii: CD-18-0484. doi: 10.1158/2159-8290.CD-18-0484. [Epub ahead of print]. PMID: 30093503.
Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, Mahale S, Davies KD, Aisner DL, Pilling AB, Berge EM, Kim J, Sasaki H, Park S, Kryukov G, Garraway LA, Hammerman PS, Haas J, Andrew SW, Lipson D, Stephens PJ, Miller VA, Varella-Garcia M, Jänne PA, Doebele RC. Oncogenic and drug sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013 Nov;19(11):1469-72. PMCID: PMC3823836.
Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, Jimeno A, Varella-Garcia M, Aisner DL, Li Y, Stephens PJ, Morosini D, Tuch BB, Fernandes M, Nanda N, Low JA. An oncogenic NTRK fusion in a soft tissue sarcoma patient with response to the tropomyosin-related kinase (TRK) inhibitor LOXO-101. Cancer Discov. 2015 Oct;5(10):1049-57. PMCID: PMC4635026.
Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018 Feb 22;378(8):731-739. doi: 10.1056/NEJMoa1714448. PMID: 29466156.
Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, Taylor M, Shaw AT, Montez S, Meric-Bernstam F, Smith S, Tuch BB, Ebata K, Cruickshank S, Cox MC, Burris HA 3rd, Doebele RC. Larotrectinib in adult patients with solid tumours: a multicentre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Jan 8. doi: 10.1093/annonc/mdy539. [Epub ahead of print] PMID: 30624546
Vaishnavi A, Schubert L, Rix U, Marek LA, Le AT, Keysar S, Glogowska MJ, Smith MA, Kako SL, Sumi NJ, Davies KD, Ware KE, Varella-Garcia M, Haura EB, Jimeno A, Heasley LE, Aisner DL, Doebele RC. EGFR mediates responses to small molecule drugs targeting oncogenic fusion kinases. Cancer Res. 2017 Jul 1;77(13):3551-3563. PMID: 28428274.
Blakely CM, Watkins TBK, Wu W, Gini B, Chabon JJ, McCoach CE, McGranahan N, Wilson GA, Birkbak NJ, Olivas VR, Rotow J, Maynard A, Wang V, Gubens MA, Banks KC, Lanman RB, Caulin AF, St John J, Cordero AR, Giannikopoulos P, Simmons AD, Mack PC, Gandara DR, Husain H, Doebele RC, Riess JW, Diehn M, Swanton C, Bivona TG. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet. 2017 Dec;49(12):1693-1704. doi: 10.1038/ng.3990.PMID: 29106415. PMCID: PMC5709185.
NIH/NCI R01 CA193935 - The role of EGFR as a mechanism of therapeutic resistance in gene fusion positive lung cancer.
Department of Defense, Lung Cancer Research Program, Translational Partnership Award - Rapid TKI-Induced Inflammatory Signaling as a Modulator of Initial Therapeutic Response
NIH/NCI P50 CA058187 - SPORE in Lung Cancer
Funding from the Dudley Family
Funding from the Christine J. Burge Endowment for Lung Cancer Research at the University of Colorado Cancer Center
Funding from the Robert and Kevin Hanlon Foundation
Eamon M. Berge, MD
Kurtis D. Davies, PhD
University of Colorado
Caroline McCoach, MD, PhD
Sarah Nelson, PhD
University of Colorado
Amanda Pilling, PhD
Henry Ford Cancer Institute
Laura Schubert, PhD
University of Colorado
Aria Vaishnavi, PhD
University of Utah
Andrew J. Weikhardt, MD
Senior Clinical Research Fellow
Olivia Newton-John Cancer Research Institute
Robert C. Doebele, MD, PhD
Nan Chen, BS
Adriana Estrada-Bernal, PhD
Paul Grewe, BA
Professional Research Assistant
Anh Le, BA
Tara Peters, PhD
Post Doctoral Fellow