Pasi A Jänne

Dana-Farber Cancer Institute, Boston, Massachusetts, United States

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Publications (244)2901.88 Total impact

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    ABSTRACT: There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; 160(5):977-989. DOI:10.1016/j.cell.2015.01.042 · 32.24 Impact Factor
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    ABSTRACT: KRAS mutations are detected in 25% of non-small cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. Eligible patients with histologically-confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomized 2:1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary endpoint was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. 129 patients with KRAS-mutant NSCLC were randomized; 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P=0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P=0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P=1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. Trametinib showed similar PFS and response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 02/2015; 26(5). DOI:10.1093/annonc/mdv072 · 7.04 Impact Factor
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    Amanda J Redig · Pasi A Jänne ·

    Journal of Clinical Oncology 02/2015; 33(9). DOI:10.1200/JCO.2014.59.8433 · 18.43 Impact Factor
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    ABSTRACT: Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9–13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer.
    The Lancet Oncology 12/2014; 15(13):1433-41. DOI:10.1016/S1470-2045(14)70461-9 · 24.69 Impact Factor
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    ABSTRACT: Introduction: Patients with stage III non-small-cell lung cancer and poor performance status and/or weight loss do not seem to benefit from standard therapy. Based on the preclinical interaction between epidermal growth factor receptor inhibitors and radiation, we designed a trial of induction chemotherapy followed by thoracic radiotherapy and concurrent erlotinib. Methods: Patients with poor-risk unresectable stage III non-small-cell lung cancer received two cycles of carboplatin at an AUC of 5 and nab-paclitaxel at 100 mg/m on days 1 and 8 every 21 days, followed by erlotinib administered concurrently with thoracic radiotherapy. Maintenance was not permitted. Molecular analysis was performed in available specimens. Seventy-two eligible patients were required to test whether the 1-year survival rate was less than 50% or greater than or equal to 65% with approximately 90% power at a significance level of 0.10. Results: From March 2008 to October 2011, 78 patients were enrolled, three of whom were ineligible. The median age was 68 (range, 39-88) and 32% were aged greater than or equal to 75 years. Patients were evenly distributed between stages IIIA and IIIB and the majority had performance status 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the prespecified target for significance. Conclusions: Patients with poor-risk stage III non-small-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2014; 10(1). DOI:10.1097/JTO.0000000000000347 · 5.28 Impact Factor
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    ABSTRACT: Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with, number NCT01360554. Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. Pfizer. Copyright © 2014 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 11/2014; 15(12):1369-78. DOI:10.1016/S1470-2045(14)70452-8 · 24.69 Impact Factor

  • International journal of radiation oncology, biology, physics 11/2014; 90(5):S71. DOI:10.1016/j.ijrobp.2014.08.304 · 4.26 Impact Factor
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    ABSTRACT: The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
    Proceedings of the National Academy of Sciences 10/2014; 111(45). DOI:10.1073/pnas.1403438111 · 9.67 Impact Factor
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    ABSTRACT: Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.
    Nature Chemical Biology 10/2014; 10(12). DOI:10.1038/nchembio.1658 · 13.00 Impact Factor
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    ABSTRACT: Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.
    New England Journal of Medicine 10/2014; 371(15):1426-1433. DOI:10.1056/NEJMoa1403352 · 55.87 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):3716-3716. DOI:10.1158/1538-7445.AM2014-3716 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):2371-2371. DOI:10.1158/1538-7445.AM2014-2371 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):939-939. DOI:10.1158/1538-7445.AM2014-939 · 9.33 Impact Factor
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    Alexis B Cortot · Pasi A Jänne ·
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    ABSTRACT: The discovery of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has allowed the identification of a subset of patients whose tumours are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). Despite the efficacy and superiority of EGFR TKIs over chemotherapy as first-line therapy, all patients will ultimately develop progressive disease, with a median of 9-13 months progression-free survival. A better understanding of the molecular mechanisms underlying resistance to EGFR TKIs can help design new drugs and therapeutic strategies to overcome resistance. This has been illustrated by the new generation TKIs that are effective on the T790M mutation, which is the most frequent mechanism of acquired resistance to EGFR TKIs. In this article, we will address the main molecular mechanisms of primary and acquired resistance to EGFR TKIs in EGFR-mutant NSCLC.
    European Respiratory Review 09/2014; 23(133):356-66. DOI:10.1183/09059180.00004614
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    ABSTRACT: MET targeted therapies are under clinical evaluation for non-small-cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKI) against MET have varying degrees of specificity. Tivantinib (ARQ 197) is reported to be a non-ATP competitive selective MET inhibitor. We aimed to compare the activity of tivantinib to other MET TKIs in a panel of NSCLC cell lines classified by their MET dependency and characterized by different relevant genotypes. A549, H3122, PC9 and HCC827, their respective resistant clones PC9 GR4 and HCC827 GR6 and the MET amplified cell lines H1993 and EBC-1 were treated in vitro with tivantinib, crizotinib or PHA-665752. Crizotinib and PHA-665752 showed growth inhibition restricted to MET dependent cell lines. The pattern of activity was related to MET inhibition and downstream signaling inhibition of AKT and ERK1/2, inducing G0/G1 cycle arrest and apoptosis. In contrast to crizotinib and PHA-665752, tivantinib possessed more potent anti-proliferative activity that was not restricted to only MET dependent cell lines. Tivantinib did not inhibit cellular MET activity nor inhibit phosphorylation of downstream effects such as AKT or ERK1/2 in either MET dependent or independent cell lines. Cell cycle analysis demonstrated that tivantinib induced a G2/M arrest and induced apoptosis. Tivantinib but not crizotinib effected microtubule dynamics, disrupting mitotic spindles by a mechanism consistent with it functioning as a microtubule depolymerizer. Tivantinib activity is independent of MET signaling in NSCLC and suggests alternative mechanisms of action that should be considered when interpreting the results from on-going clinical studies.
    Molecular Oncology 08/2014; 9(1). DOI:10.1016/j.molonc.2014.08.011 · 5.33 Impact Factor
  • Adrian G. Sacher · Pasi A. Jänne · Geoffrey R. Oxnard ·
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    ABSTRACT: The widespread adoption of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the first-line treatment of patients with advanced EGFR-mutated non-small cell lung cancer has resulted in acquired tyrosine kinase inhibitor resistance becoming a ubiquitous clinical problem. The identification of specific mechanisms of acquired resistance has allowed a better understanding of the biology and natural history of resistant disease, but is only now starting to impact treatment decisions. Strategies for managing acquired resistance in patients with advanced non-small cell lung cancer are complex and must be adapted to the individual characteristics of each patient's cancer. Although combination chemotherapy is the presumed standard of care for most patients, prospective trial data are lacking, highlighting the importance of offering patients participation in clinical trials in this setting. Emerging data from trials of third-generation mutant-specific EGFR kinase inhibitors suggests particular promise with this class of agents. Cancer 2014. © 2014 American Cancer Society.
    Cancer 08/2014; 120(15). DOI:10.1002/cncr.28723 · 4.89 Impact Factor
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    ABSTRACT: Objectives The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined. Materials and methods A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990-2012. Results 300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stage I-III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4-32), compared to 3 (1%) patients with typical carcinoid (range, 8-12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum-etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5 year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 m median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 m median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6-72 months). Conclusions These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy.
    Lung Cancer 08/2014; 86(2). DOI:10.1016/j.lungcan.2014.08.012 · 3.96 Impact Factor
  • Cloud P. Paweletz · Pasi A. Jänne ·
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    ABSTRACT: Tumor biopsies remain the gold standard for the evaluation of genetic changes in tumors either at diagnosis or after treatment with targeted therapies. However, this is not always feasible and can seldom be performed more than once. Noninvasive techniques that measure the allelic burden in blood have the potential to realize genotype‐directed cancer therapy. These technologies can potentially be used for noninvasive tumor genotyping and also provide an opportunity for disease monitoring. Several non‐invasive genotyping technologies are currently under development and being evaluated in patients treated with targeted therapies.
    Cancer 08/2014; 120(24). DOI:10.1002/cncr.28967 · 4.89 Impact Factor
  • Matthew G Oser · Pasi A Jänne ·

    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 07/2014; 9(7):e51-3. DOI:10.1097/JTO.0000000000000163 · 5.28 Impact Factor
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    ABSTRACT: Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers.
    Cell Reports 06/2014; 7(6). DOI:10.1016/j.celrep.2014.05.039 · 8.36 Impact Factor

Publication Stats

29k Citations
2,901.88 Total Impact Points


  • 2000-2015
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 1999-2015
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 2008-2014
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2003-2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2009
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2007
    • Sungkyunkwan University
      Sŏul, Seoul, South Korea
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2006
    • Rush Medical College
      Chicago, Illinois, United States
  • 1994-1995
    • University of Pennsylvania
      • Department of Genetics
      Philadelphia, PA, United States
  • 1992
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States