Timothy F. Burns, MD, PHD
Assistant Professor of Medicine

Dr. Burns is Assistant Professor of Medicine, Division of Hematology-Oncology Associate Program Director for Research, UPMC Hematology/Oncology Fellowship Program Member, UPMC Hillman Cancer Center, Cancer Biology Program .

Office Location:
Hillman Cancer Center Research Pavilion
5117 Centre Ave, Suite 2.18e
Pittsburgh, PA 15213-1863

Contact Information:
Office Telephone: 412-864-7859
Fax: 412-623-7768
Email: burnstf@upmc.edu

Research Interests

Lung cancer is the leading cause of cancer death in the United States and worldwide. Recent advances in the treatment of non-small cell lung carcinoma (NSCLC) have come from recognition that NSCLC is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms. This paradigm is typified by the recent progress made in the treatment of patients with EGFR-mutant and EML4-ALK translocation-driven adenocarcinomas of the lung with tyrosine kinase inhibitors targeting these oncogenes. Unfortunately, resistance to these targeted therapies is inevitable and new therapeutic strategies to treat these patients are clearly needed. Furthermore, little progress has been made in the treatment of patients with the most frequently observed driver oncogene, mutant KRAS. KRAS is mutated in approximately 25% of all NSCLC, and patients with this mutation have an increased risk of recurrence in early stage disease and have a worse prognosis with metastatic disease.

My research and clinical interests revolve around the development of targeted therapies for KRAS-mutant NSCLC as well as novel strategies to overcome resistance to targeted therapies for EGFR-mutant and MET-altered NSCLC. My two main research themes are 1) novel pre-clinical target validation and drug development (TWIST1 in oncogene driven NSCLC and TKI resistance) (Fig 1); and 2) elucidating mechanisms of resistance for targeted inhibitors to develop rationale therapeutic combinations that can be tested in the clinic (Hsp90 and ERK1/2 inhibitors) (Figs. 2-3).

The first line of research in my laboratory focuses on the role of the epithelial mesenchymal transition transcription factor TWIST1 in oncogene-driven NSCLC. We have demonstrated the TWIST1 is essential for lung tumorigenesis for several key oncogenic drivers including KRAS mutant, EGFR mutant and MET mutant/amplified NSCLC. Furthermore, we have demonstrated that TWIST1 overexpression leads to resistance to EGFR and MET targeted therapies. We are currently examining the mechanism(s) through which this occurs and developing therapeutic combinations to overcome this resistance (Fig. 1). In addition, we are now exploring whether targeting the HGF-MET-TWIST1 pathway can be an effective strategy for preventing or treating lung brain metastases. Importantly, we have developed a novel TWIST1 inhibitor which serves a tool compound for our therapeutic studies and serves as the basis for our current drug screening efforts in order to develop a TWIST1 inhibitor that we can translate to the clinic.

The second line of research in my lab focuses on studying the mechanisms of resistance to targeted agents currently in phase 1 and 2 trials to develop rationale therapeutic combinations in the clinic. This is typified by our previous work with Hsp90 inhibitors (Fig. 2) and ongoing work on ERK inhibitors (Fig. 3). We previously studied why resistance occurs to the Hsp90 inhibitor (Hsp90i), ganetespib in KRAS-mutant NSCLC. The goal of this work was to understand Hsp90i resistance so that we could develop a rationally designed Hsp90i combination for the clinic which can prevent or overcome resistance. We found that the ERK-p90RSK-CDC25C pathway plays a key role in resistance to Hsp90 inhibitors through bypass of a G2/M checkpoint. These data suggest that the combination of an ERK inhibitor with an Hsp90 inhibitor maybe effective in KRAS mutant NSCLC (Fig. 2).

As reactivation of ERK appears to be a central node of resistance to EGFR TKIs in the clinic, we are examining whether use of the first clinical ERK1/2 inhibitor, LY3214996 in combination with EGFR TKIs can overcome EGFR TKI resistance due to diverse mechanisms of resistance including 2nd site EGFR mutations or bypass signaling pathways including EMT-TFs (Fig 3). These ongoing studies will generate the preclinical rationale for a clinical trial looking at the combination in EGFR mutant patients who have progressed on osimertinib and help define the patient population that will most benefit from the combination.

Selected Publications

View Dr. Burns' publications on PubMed

  1. Tran PT*, Shroff EH*, Burns TF*, Thiyagarajan S, Das ST, Zabuawala T, Chen J, Cho YJ, Luong R, Tamayo P, Salih T, Aziz K, Adam SJ, Vicent S, Nielsen CH, Withofs N, Sweet-Cordero A, Gambhir SS, Rudin CM, Felsher DW. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis. PLoS Genet. 2012;8(5):e1002650. doi: 10.1371/journal.pgen.1002650. PubMed PMID: 22654667; PMCID: PMC3360067.
  2. Burns TF, Dobromilskaya I, Murphy SC, Gajula RP, Thiyagarajan S, Chatley SN, Aziz K, Cho YJ, Tran PT, Rudin CM. Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer. Mol Cancer Res. 2013;11(4):329-38. doi: 10.1158/1541-7786.MCR-12-0456. PubMed PMID: 23364532; PMCID: PMC3631276.
  3. Chatterjee S, Huang EH, Christie I, Kurland BF, Burns TF. Acquired resistance to the Hsp90 inhibitor, ganetespib, in KRAS-mutant NSCLC is mediated via reactivation of the ERK-p90RSK-mTOR signaling network. Mol Cancer Ther. 2017;16(5):793-804. doi: 10.1158/1535-7163.MCT-16-0677. PubMed PMID: 28167505; PMCID: PMC5418121.
  4. Chatterjee S, Huang EH, Christie I, Burns TF. Reactivation of the p90RSK-CDC25C pathway leads to bypass of the ganetespib-induced G2-M arrest and mediates acquired resistance to ganetespib in KRAS-mutant NSCLC. Mol Cancer Ther. 2017;16(8):1658-68. doi:
  5. Yochum ZA, Cades J, Mazzacurati L, Neumann NM, Khetarpal SK, Chatterjee S, Wang H, Attar MA, Huang EH, Chatley SN, Nugent K, Somasundaram A, Engh JA, Ewald AJ, Cho YJ, Rudin CM, Tran PT, Burns TF. A first-in-class TWIST1 inhibitor with activity in oncogene-driven lung cancer. Mol Cancer Res. 2017;15(12):1764-76. doi: 10.1158/1541-7786.MCR-17-0298. PubMed PMID: 28851812; PMCID: PMC5712248.
  6. Godse NR, Khan N, Yochum ZA, Gomez-Casal R, Kemp C, Shiwarski DJ, Seethala RS, Kulich S, Seshadri M, Burns TF, Duvvuri U. TMEM16A/ANO1 inhibits apoptosis via downregulation of bim expression. Clin Cancer Res. 2017;23(23):7324-32. doi: 10.1158/1078-0432.CCR-17-1561. PubMed PMID: 28899969; PMCID: PMC5898434.
  7. Chen G, Gao C, Gao X, Zhang DH, Kuan SF, Burns TF, Hu J. Wnt/beta-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer. Mol Cancer Ther. 2017. doi: 10.1158/1535-7163.MCT-17-0561. PubMed PMID: 29167314.
  8. Han J, Goldstein LA, Hou W, Chatterjee S, Burns TF, Rabinowich H. HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC. Autophagy. 2018:1-14. doi: 10.1080/15548627.2018.1434471. PubMed PMID: 29561705.
  9. Yochum ZA, Cades J, Wang H, Chatterjee S, Simons BW, O'Brien JP, Khetarpal SK, Lemtiri-Chlieh G, Myers KV, Huang EH, Rudin CM, Tran PT, Burns TF. Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene. 2019;38(5):656-70. doi: 10.1038/s41388-018-0482-y. PubMed PMID: 30171258; PMCID: PMC6358506
  10. Gerber DE, Camidge DR, Morgensztern D, Cetnar J, Kelly RJ, Ramalingam SS, Spigel DR, Jeong W, Scaglioni PP, Zhang S, Li M, Weaver DT, Vaikus L, Keegan M, Horobin JC, Burns TF. Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands). 2020;139:60-7. doi: 10.1016/j.lungcan.2019.10.033. PubMed PMID: 31739184; PMCID: PMC6942685.