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Mechanisms of Osimertinib Resistance in EGFR Mutant Lung Cancer
S1546
Journal of Thoracic Oncology
from PAMs, referred to as progression-associated neoepitopes (PAN), are associated with the highest levels of CD8+ T cell infiltration and PDL1 expression. Conclusions: Thus, frequent immune-effector cell infiltration and accompanying adaptive immune suppression suggest specific immune antigen recognition of PAN. Future longitudinal studies will define the natural history of pulmonary premalignancy allowing immune-interception of high-risk lesions, thus preventing progression to invasive disease.
1
1
composed of a coordinating center and individual sites conducting research in therapeutic development, mechanisms of resistance, and the prevention and early detection of SCLC. The coordinating center and two projects (with others pending) were awarded after the first round. An overview of the current NCI SCLC portfolio will be presented.
Mechanisms of Osimertinib Resistance in EGFR Mutant Lung Cancer D. Westover, H. Qiao, E. Ichihara, C.B. Meador, C.M. Lovly Vanderbilt University Medical Center, Nashville, TN, US
Genomic Landscape of Atypical Adenomatous Hyperplasia and Their Progression to Lung Adenocarcinomas 1
Vol. 12 No. 8S
1
1
S. Sivakumar, F.A. San Lucas, T.L. McDowell, W. Lang, L. Xu, J. Fujimoto,1 J. Zhang,1 I.I. Wistuba,1 F.A. Futreal,1 J. Fukuoka,2 Y. Yatabe,3 S. Dubinett,4 A. Spira,5 J. Fowler,1 E. Hawk,1 P. Scheet,1 H. Kadara1,6 1The University of Texas MD Anderson Cancer Center, Houston, TX, US, 2Nagasaki University, JP, 3University of California Los Angeles, Los Angeles, CA, US, 4Aichi Cancer Center, JP, 5Boston University, Boston, MA, US, 6The American University of Beirut, Beirut, LB Background: There is a paucity of knowledge about the molecular pathogenesis in atypical adenomatous hyperplasia (AAH), the only known premalignant lesion to lung adenocarcinomas (LUAD). We performed deep targeted DNA sequencing of matched AAH, LUAD and normal tissues from 22 patients, and transcriptome sequencing in a subset of 17 patients, in order to better understand the mutation and expression profiles governing the initiation and progression of AAH to invasive LUAD. Results: BRAF somatic mutations were found in 23% of AHHs, and of these 80% exhibited driver EGFR mutations in their matched LUADs. KRAS was the second most frequently mutated gene in AAH (18%), all smokers and exclusive of BRAF mutations. Integrative analysis revealed genes preferentially expressed in KRAS- and BRAFmutant AAH or common to both. Gene sets associated with activated pro-tumor (Th2; CCR2, CTLA-4) and reduced anti-tumor (Th1; IL12A, GZMB, TBX21) immune functioning were observed in the development and progression of AAH. Conclusions: Our findings suggest disparate pathways of LUAD pathogenesis based on driver mutation status in the AAH. We also elucidate the importance of immune regulation in the development and progression of AAH to invasive tumors, suggesting immune-based personalized preventive strategies.
Small Cell Lung Cancer and the Recalcitrant Cancer Research Act O.W. Lindwasser, P. Ujhazy, M.A. Antman, S.A. Prindiville National Cancer Institute, Bethesda, MD, US Background: The Recalcitrant Cancer Research Act of 2012 called on the National Cancer Institute (NCI) to develop plans for research on cancers that have a 5-year relative survival of less than 20% and are estimated to cause the deaths of at least 30,000 individuals in the United States per year. Small cell lung cancer (SCLC) was among the cancers identified by the NCI and a working group of international experts in SCLC met in July 2013 to advise the NCI on recommendations to advance research in SCLC. The scientific framework for SCLC, detailing the findings of the working group, was submitted to Congress in June 2014. Results: The scientific framework provides the background, rationale, and implementation plans for five initiatives to expand SCLC research: Better Research Tools for the Study of SCLC; Comprehensive Genomic Profiling of SCLC; New Diagnostic Approaches for SCLC; Therapeutic Development Efforts; and Mechanisms Underlying Both High Rate of Initial Response and Rapid Emergence of Drug and Radiation Resistance. Conclusions: As part of the NCI’s implementation of these initiatives, three program announcements were released in December 2015 establishing the SCLC Consortium, to be
Background: Osimertinib is a mutant-selective EGFR TKI and the first approved EGFR inhibitor that is effective against tumors with the T790M gatekeeper mutation. Unfortunately, as with other EGFR TKIs, resistance inevitably develops. Using a variety of biochemical, pharmacological, and cell-based approaches, our group is working to identify mechanisms of resistance to osimertinib. Results: Here, we give an update on potential resistance mechanisms that we are investigating, including novel tertiary EGFR mutations and YES1 amplification, and discuss recent clinical developments. We will also describe our on-going efforts to complete a high-throughput drug screen in osimertinib-resistant cell lines. A library of over 2,300 drugs was assembled which encompasses a diverse scope of targets, including signaling kinases, epigenetic modulators, cell metabolism, GPCRs, ion channels, and inflammation modulators. This chemical diversity allows us to broaden our investigation beyond the traditional signaling pathways thought to be involved in EGFR TKI resistance. We screened this library to identify clinically relevant compounds which synergize with osimertinib in the setting of first-line and second-line osimertinib resistance. Conclusions: We are continuing to expand our understanding of osimertinib resistance by identifying target-dependent as well as target-independent mechanisms. Overall, our goals are to identify strategies to delay or reverse osimertinib resistance and to inform clinical trial development.
Targeting Residual Disease in Oncogene-Driven NSCLC C.E. McCoach, D.T. Merrick, D.L. Aisner, P.A. Bunn, D.R. Camdige, L.E. Heasley, R.C. Doebele University of Colorado Cancer Center, Denver, CO, US Background: Recent analyses in patients with ALK positive nonesmall cell lung cancer (NSCLC) treated with crizotinib have demonstrated an association between larger depth of response and improved progression free survival and overall survival. These data suggest that reduction of this residual disease compartment may present an alternative strategy to improve survival and is consistent with the idea that this residual disease compartment is the origin of tumor cells that ultimately drive disease progression. Thus, studies analyzing the characteristics of this reservoir are needed to determine how to target this compartment. Results: We have developed two clinical trials to facilitate the characterization of the residual disease compartment in patients with NSCLC. The first trial will accrue patients with early stage ALK, ROS1 or MET mutated NSCLC. Patients will receive 6 weeks of neoadjuvant treatment with crizotinib followed by surgical resection. The second trial will enroll patients with stage IV EGFR mutated NSCLC. Patients will undergo a pre-treatment biopsy and a repeat biopsy of the same lesion two weeks after starting treatment with an EGFR inhibitor. Tumor specimens from both studies will be evaluated with RNA Seq, multiparameter protein expression analysis and proximity ligation assays to identify early adaptive mechanisms of cell survival in the setting of oncogene-targeted therapy. Conclusions: Similar to post-progression biopsies that allowed identification of mechanisms of acquired resistance, these clinical trials will facilitate identification of early escape mechanisms from targeted therapy.
Journal of Thoracic Oncology
from PAMs, referred to as progression-associated neoepitopes (PAN), are associated with the highest levels of CD8+ T cell infiltration and PDL1 expression. Conclusions: Thus, frequent immune-effector cell infiltration and accompanying adaptive immune suppression suggest specific immune antigen recognition of PAN. Future longitudinal studies will define the natural history of pulmonary premalignancy allowing immune-interception of high-risk lesions, thus preventing progression to invasive disease.
1
1
composed of a coordinating center and individual sites conducting research in therapeutic development, mechanisms of resistance, and the prevention and early detection of SCLC. The coordinating center and two projects (with others pending) were awarded after the first round. An overview of the current NCI SCLC portfolio will be presented.
Mechanisms of Osimertinib Resistance in EGFR Mutant Lung Cancer D. Westover, H. Qiao, E. Ichihara, C.B. Meador, C.M. Lovly Vanderbilt University Medical Center, Nashville, TN, US
Genomic Landscape of Atypical Adenomatous Hyperplasia and Their Progression to Lung Adenocarcinomas 1
Vol. 12 No. 8S
1
1
S. Sivakumar, F.A. San Lucas, T.L. McDowell, W. Lang, L. Xu, J. Fujimoto,1 J. Zhang,1 I.I. Wistuba,1 F.A. Futreal,1 J. Fukuoka,2 Y. Yatabe,3 S. Dubinett,4 A. Spira,5 J. Fowler,1 E. Hawk,1 P. Scheet,1 H. Kadara1,6 1The University of Texas MD Anderson Cancer Center, Houston, TX, US, 2Nagasaki University, JP, 3University of California Los Angeles, Los Angeles, CA, US, 4Aichi Cancer Center, JP, 5Boston University, Boston, MA, US, 6The American University of Beirut, Beirut, LB Background: There is a paucity of knowledge about the molecular pathogenesis in atypical adenomatous hyperplasia (AAH), the only known premalignant lesion to lung adenocarcinomas (LUAD). We performed deep targeted DNA sequencing of matched AAH, LUAD and normal tissues from 22 patients, and transcriptome sequencing in a subset of 17 patients, in order to better understand the mutation and expression profiles governing the initiation and progression of AAH to invasive LUAD. Results: BRAF somatic mutations were found in 23% of AHHs, and of these 80% exhibited driver EGFR mutations in their matched LUADs. KRAS was the second most frequently mutated gene in AAH (18%), all smokers and exclusive of BRAF mutations. Integrative analysis revealed genes preferentially expressed in KRAS- and BRAFmutant AAH or common to both. Gene sets associated with activated pro-tumor (Th2; CCR2, CTLA-4) and reduced anti-tumor (Th1; IL12A, GZMB, TBX21) immune functioning were observed in the development and progression of AAH. Conclusions: Our findings suggest disparate pathways of LUAD pathogenesis based on driver mutation status in the AAH. We also elucidate the importance of immune regulation in the development and progression of AAH to invasive tumors, suggesting immune-based personalized preventive strategies.
Small Cell Lung Cancer and the Recalcitrant Cancer Research Act O.W. Lindwasser, P. Ujhazy, M.A. Antman, S.A. Prindiville National Cancer Institute, Bethesda, MD, US Background: The Recalcitrant Cancer Research Act of 2012 called on the National Cancer Institute (NCI) to develop plans for research on cancers that have a 5-year relative survival of less than 20% and are estimated to cause the deaths of at least 30,000 individuals in the United States per year. Small cell lung cancer (SCLC) was among the cancers identified by the NCI and a working group of international experts in SCLC met in July 2013 to advise the NCI on recommendations to advance research in SCLC. The scientific framework for SCLC, detailing the findings of the working group, was submitted to Congress in June 2014. Results: The scientific framework provides the background, rationale, and implementation plans for five initiatives to expand SCLC research: Better Research Tools for the Study of SCLC; Comprehensive Genomic Profiling of SCLC; New Diagnostic Approaches for SCLC; Therapeutic Development Efforts; and Mechanisms Underlying Both High Rate of Initial Response and Rapid Emergence of Drug and Radiation Resistance. Conclusions: As part of the NCI’s implementation of these initiatives, three program announcements were released in December 2015 establishing the SCLC Consortium, to be
Background: Osimertinib is a mutant-selective EGFR TKI and the first approved EGFR inhibitor that is effective against tumors with the T790M gatekeeper mutation. Unfortunately, as with other EGFR TKIs, resistance inevitably develops. Using a variety of biochemical, pharmacological, and cell-based approaches, our group is working to identify mechanisms of resistance to osimertinib. Results: Here, we give an update on potential resistance mechanisms that we are investigating, including novel tertiary EGFR mutations and YES1 amplification, and discuss recent clinical developments. We will also describe our on-going efforts to complete a high-throughput drug screen in osimertinib-resistant cell lines. A library of over 2,300 drugs was assembled which encompasses a diverse scope of targets, including signaling kinases, epigenetic modulators, cell metabolism, GPCRs, ion channels, and inflammation modulators. This chemical diversity allows us to broaden our investigation beyond the traditional signaling pathways thought to be involved in EGFR TKI resistance. We screened this library to identify clinically relevant compounds which synergize with osimertinib in the setting of first-line and second-line osimertinib resistance. Conclusions: We are continuing to expand our understanding of osimertinib resistance by identifying target-dependent as well as target-independent mechanisms. Overall, our goals are to identify strategies to delay or reverse osimertinib resistance and to inform clinical trial development.
Targeting Residual Disease in Oncogene-Driven NSCLC C.E. McCoach, D.T. Merrick, D.L. Aisner, P.A. Bunn, D.R. Camdige, L.E. Heasley, R.C. Doebele University of Colorado Cancer Center, Denver, CO, US Background: Recent analyses in patients with ALK positive nonesmall cell lung cancer (NSCLC) treated with crizotinib have demonstrated an association between larger depth of response and improved progression free survival and overall survival. These data suggest that reduction of this residual disease compartment may present an alternative strategy to improve survival and is consistent with the idea that this residual disease compartment is the origin of tumor cells that ultimately drive disease progression. Thus, studies analyzing the characteristics of this reservoir are needed to determine how to target this compartment. Results: We have developed two clinical trials to facilitate the characterization of the residual disease compartment in patients with NSCLC. The first trial will accrue patients with early stage ALK, ROS1 or MET mutated NSCLC. Patients will receive 6 weeks of neoadjuvant treatment with crizotinib followed by surgical resection. The second trial will enroll patients with stage IV EGFR mutated NSCLC. Patients will undergo a pre-treatment biopsy and a repeat biopsy of the same lesion two weeks after starting treatment with an EGFR inhibitor. Tumor specimens from both studies will be evaluated with RNA Seq, multiparameter protein expression analysis and proximity ligation assays to identify early adaptive mechanisms of cell survival in the setting of oncogene-targeted therapy. Conclusions: Similar to post-progression biopsies that allowed identification of mechanisms of acquired resistance, these clinical trials will facilitate identification of early escape mechanisms from targeted therapy.