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S.M. Dubinett



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    MINI 02 - Immunotherapy (ID 92)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI02.09 - ERK Activation Mediates Increased PD-L1 Expression in KRAS Mutated Premalignant Human Bronchial Epithelial Cells (ID 1620)

      S.M. Dubinett

      • Abstract
      • Presentation
      • Slides

      Background:
      Immune checkpoint pathways including the PD-1/PD-L1 pathway are involved in tumor evasion from the immune system. Elevated PD-L1 expression in tumor cells inhibits tumor-infiltrating T cell function and may be associated with poor prognosis in lung cancer patients. There is increasing interest in developing immunotherapies that block the immunosuppressive effects of checkpoint pathways such as PD-L1, and identifying patients who may benefit from PD-L1 blockade. Activating KRAS mutations are common driver mutations in non-small cell lung carcinoma. Patients with mutated KRAS demonstrate less benefit from adjuvant chemotherapy and resistance to tyrosine kinase inhibitors. The effect of cancer cell driver mutations on immune checkpoint immune regulation is poorly understood. While recent clinical trials have suggested better response to PD-1 blockade in KRAS mutation subjects, it is unclear if this clinical finding is directly driven by KRAS regulating the PD-1/PD-L1 pathway with resultant improved efficacy to anti-PD-L1 immunotherapy or if the presence of a KRAS mutation is merely a surrogate marker of the overall mutational load and tumor immunogenicity. KRAS mutations are known to activate the RAF-MEK-ERK pathway. We hypothesize that KRAS mutation directly regulates the PD-1/PD-L1 pathway through ERK activation.

      Methods:
      Immortalized human bronchial epithelial cells (HBEC-vector control), KRAS–mutated (KRAS[v12]) HBEC cells (HBEC-KRAS), p53 knockdown HBEC cells (HBEC-p53), and p53 knockdown/KRAS mutated cells (HBEC-p53/KRAS) were used to assess mRNA and/or surface protein expression levels of immune checkpoints including Lag-3, Tim-3, PD-L1 and PD-L2 by real time-qPCR (RT-qPCR) and flow cytometry, respectively. HBEC-vector and HBEC-KRAS cells were treated with MEK (ERK kinase) inhibitor (PD0325901) at 1µM for 24hrs and evaluated for mRNA and surface protein expression of PD-L1. The premalignant HBEC cell lines were used instead of human lung cancer cell lines in order to assess the role of KRAS mutation in isolation without other mutations.

      Results:
      PD-L1 and PD-L2 mRNA levels increased 2.4 fold (p<0.001) and 3.6 (p<0.001) fold in comparing HBEC-KRAS to HBEC-vector (wild-type) cells, while Lag-3 and Tim-3 mRNA expression levels were unchanged. Based on mean fluorescence intensity on flow cytometry, cell surface PD-L1 protein expression level was 2.2 and 1.6 fold higher in HBEC-KRAS and HBEC-p53/KRAS, respectively, compared to HBEC-vector cells. There was no increase in surface PD-L1 expression in HBEC-p53 cells compared to HBEC-vector control, suggesting that p53 mutation did not alter PD-L1 expression in HBEC-p53/KRAS cells. With MEK inhibition, PD-L1 mRNA levels decreased 10 and 11 fold in HBEC-vector and HBEC-KRAS cells, respectively. Analogously, PD-L1 surface protein levels were reduced 2.7 fold in HBEC-vector and HBEC-KRAS cells, respectively. These findings suggest that ERK activation mediates intrinsic expression and KRAS mutation mediates over-expression of PD-L1 mRNA and protein.

      Conclusion:
      Here, we demonstrate that PD-L1 expression is elevated in premalignant KRAS mutated human bronchial epithelial cells, and ERK activation mediates constitutive and KRAS mutation driven up-regulation of PD-L1 in these cells. Our findings suggest that KRAS mutation may directly regulate the PD-1/PD-L1 immune checkpoint pathway. Further understanding of KRAS driven molecular pathways that modulate immune checkpoints may elucidate therapeutic targets for potential combinational drugs to PD-L1 inhibition.

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    MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI03.01 - Prior TKI Therapy in NSCLC EGFR Mutant Patients Associates with Lack of Response to Anti-PD-1 Treatment (ID 2172)

      S.M. Dubinett

      • Abstract
      • Presentation
      • Slides

      Background:
      Programmed cell death-1 (PD-1) inhibitors have shown significant potential to induce durable responses in non-small cell lung cancer (NSCLC). Although responses have been seen in patients (pts) whose tumors harbor epidermal growth factor receptor (EGFR) mutations (EGFRm), data to date with inhibitors of PD-1, or its ligand PD-L1, suggest that responses are less frequent in EGFRm NSCLC. Studies in which EGFRm pts receive EGFR tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors in sequence or concurrently are being conducted. However, based on the high response rate with EGFR TKIs in EGFRm pts, PD-1 inhibition does not precede the EGFR TKIs in these study designs.

      Methods:
      We evaluated data from our experience at UCLA as part of the KEYNOTE-001 clinical trial, in which pts received pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Early in the trial, an amendment excluded EGFRm, EGFR TKI naïve pts, however a subsequent amendment allowed such pts if their mutation was non-sensitizing to approved EGFR TKIs. Although the trial employed central radiographic assessment by RECIST v1.1 (available to the sponsor but not the sites), clinical decisions and the assessment we describe were based on investigator-assessed immune-related response criteria. Groups were compared using Fisher’s exact test. Western blot was performed using standard techniques, exposing human non-small cell lung cancer cell lines HCC-827, H1975, Calu3 and H460 to erlotinib or afatinib at 1µM or control using the antibody PD-L1 mAb #1368 (Cell Signaling) and α-tubulin antibody #2144 (Cell Signaling).

      Results:
      We enrolled 29 EGFRm pts. 2 of 3 EGFR TKI naïve pts experienced a partial response (PR) compared to 1 of 26 enrolled after a prior EGFR TKI (p<0.001). 18 of these 29 pts had a 9 week scan. Of these, PR was seen in both EGFR TKI naïve pts (one L858R mutation and one exon 20 insertion) compared to 1 of 16 enrolled after a prior EGFR TKI (p<0.001). Of note, a similar trend of increased responses in EGFR TKI naïve pts was not seen in EGFR wild type pts. In vitro experiments using erlotinib and afatinib showed unchanged PD-L1 levels in cell lines not inhibited by the EGFR TKI used, but reduced PD-L1 in EGFRm cell lines inhibited by the TKI. Of note, the only responder among the EGFR TKI-treated EGFRm pts was one of only 4 of the 16 scanned post-TKI pts who had a non-sensitizing mutation. So, 0 of 22 EGFRm pts with a sensitizing mutation responded after an EGFR TKI.

      Conclusion:
      A retrospective analysis in EGFRm NSCLC showed a strong correlation between response and lack of prior EGFR TKI treatment. PD-L1 levels decrease in response to an EGFR TKI in cell lines sensitive to the TKI. Immunohistochemistry evaluating the presence and location of relevant proteins and immune effector cells are ongoing as is whole exome sequencing. These results have implications for the design of clinical trials of PD-1 inhibitors in EGFRm pts. Supported by: 1K23CA149079, One Ball Matt Memorial Golf Tournament, Kasdan Family

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    MS 25 - Lung Carcinogenesis (ID 43)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
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      MS25.05 - Premalignant Lesions: Cytokines and Microenvironment (ID 1962)

      S.M. Dubinett

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 13 - Immunotherapy Biomarkers (ID 104)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL13.02 - Characterization of PD-L1 Expression Related to Unique Genes in NSCLC Tissue Samples (ID 2173)

      S.M. Dubinett

      • Abstract
      • Presentation
      • Slides

      Background:
      Programmed cell death protein 1 (PD-1) receptors are members of the B7:CD28 family that interact with PD-1 ligands PD-L1 and PD-L2 to regulate cytotoxic T cell (CTL) tolerance (Freeman, J Exp Med. 2000; Latchman, Nat Immunol. 2001). Successful evasion of transformed cells from host defense is a feature of cancer (Hanahan, Cell 2011). Immune evasion can occur via the engagement of PD-1 with PD-L1 or PD-L2 (Dong, Nature Med 2002). In metastatic non-small cell lung cancer (NSCLC), PD-L1 expression has been associated with increased response to inhibitors of PD-1 (Garon, NEJM 2015). Current adjuvant cytotoxic approaches are associated with a real but small survival increases and significant toxicity. Characterization of PD-L1 expression in resected tumors could guide development of immune checkpoint based adjuvant trials.

      Methods:
      Microarray analyses were performed to assess gene expression for 320 NSCLC and 15 normal lung resection specimens profiled on the Agilent Whole Human Genome 4x44K 2-color platform. The reference sample used in the experiments was an equal mixture of 258 of the 320 NSCLC samples included in the study. Microarray data was imported into Rosetta Resolver for analysis. The Rosetta Similarity Tool (ROAST) was utilized to find genes correlated to PD-L1 expression. Both PD-L1 and the target gene had to be differentially expressed for sample to be included in computation of correlation. Cosine correlation was used as the similarity metric. Functional genomic analysis on the list of PD-L1 correlated genes was performed using tools available with the DAVID Bioinformatics resources (david.abcc.ncifcrf.gov) Survival analyses based on PD-L1 expression were performed using the Kaplan-Meier method and compared using the log-rank test. Samples with PD-L1 log(ratio) > 0 and p-value < 0.01 were classified as upregulated, samples with p-value>0.01 were classified as unchanged, and sample with log(ratio) < 0 and p-value <0.01 were classified as downregulated.

      Results:
      The reference level of PD-L1 expression among the subset of normal lung and NSCLC tissue samples was higher compared to levels seen in 503 breast cancer and 149 endometrial cancer tissue samples. Within the 320 NSCLC tissue samples, 174 unique genes are highly correlated with PD-L1 expression (r range= 0.692-0.904). 80 tissue samples (25%) had a PD-L1 log ratio > 0, and 63 tissue samples had large sets of highly correlated genes, a similar prevalence to membranous staining in half the cells in metastatic NSCLC (Garon, NEJM 2015). Functional analyses revealed that the genes significantly correlated with PD-L1 expression were involved in immune and inflammatory response. No significant difference in overall survival was noted (p=.661), but increased PD-L1 expression was clearly not associated with better outcomes.

      Conclusion:
      Within the NSCLC cohort, there is a group of patients with high expression for PD-L1 and related genes. This group does not have a better prognosis in comparison to those with typical or decreased PD-L1 expression. Due to the relationship between PD-L1 expression and response to anti-PD-1 therapy in metastatic NSCLC, this data and its correlation with other clinical characteristics of the patients can guide the design of adjuvant approaches based on immune checkpoint inhibitors.

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    ORAL 31 - PD1 Axis Inhibition (ID 143)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL31.05 - High Intratumoral T Cell Infiltration Correlated with Mutational Load and Response to Pembrolizumab in Non-Small Cell Lung Cancer (ID 2728)

      S.M. Dubinett

      • Abstract
      • Presentation
      • Slides

      Background:
      Responses to PD-1 blockade have been induced in approximately 20% of advanced non-small cell lung cancer (NSCLC) patients with progressive disease after standard therapy [Garon, NEJM 2015]. One challenge is to understand how the immune response was initiated in responding patients. Tumor mutational burden has been associated with response to PD-1 checkpoint inhibitors in NSCLC [Rizvi, Science, 2015]. In addition, studies in melanoma patient-derived tumor specimens revealed that responses to PD-1/L1 blockade rely on pre-therapy tumor infiltration of activated T effector cells [Tumeh, Nature, 2014]. We hypothesize that clonal T cell infiltration is correlated with tumor mutational load and clinical response with PD-1 blockade.

      Methods:
      We studied tumor specimens in NSCLC patients treated with pembrolizumab at UCLA on the KEYNOTE -001 clinical trial. All patients signed informed consent for the trial as well as separate specimen acquisition protocols. Responses were classified by the investigators according to irRC. DNA was extracted and whole exome sequencing was performed at the UCLA Immunogenetics Core. DNA from the same patient’s PBMC or other non-cancerous tissue was sequenced for baseline comparison. Immunohistochemistry (IHC) was done for CD8 (Clone C8/144B, Dako), CD4 (Clone SP35, Cell Marque) and PD-L1 (Clone SP142, Spring Bioscience).

      Results:
      We report results from 27 patients (14 responders, and 13 nonresponders). Significantly higher density of pre-dosing CD8+ cells (percentage of CD8+ nucleated cells) in the tumors of the responding patients was observed (mean of 17.7% in responders vs 5.6% in non-responders, p=0.02 by unpaired t test) suggestive of a pre-existing immune response. Mutational load in 5 patients (3 responders and 2 nonresponders) showed a trend towards correlation with response (mean of 19 nonsynonymous somatic mutations per MB in responders vs 6 in nonresponders, p=0.33). Interestingly, a strikingly significant correlation between mutational load and CD8 expression was observed (R[2]=0.96, p=0.003). In addition, pre-dosing tumor PD-L1 expression demonstrated a trend towards correlation with response (mean of 72.1% in responders vs 51.5% in nonresponders, p=0.07) but not with CD8 tumor infiltration (R[2]=0.05, p=0.28). No significant association of CD4+ T cell tumor infiltration with response (mean of 37.4% CD4 + cells in responders vs 27.0% in nonresponders, p=0.32) was observed.

      Conclusion:
      We observed strong correlation of pre-dosing intratumoral T cell infiltration with response and mutational load in NSCLC patients treated with pembrolizumab. Our results have direct implications for the design and interpretation of ongoing and planned immunotherapy studies for NSCLC and evaluation of potential predictive biomarkers to select patients most likely to benefit.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-063 - Exposure to IL-1β Leads to EMT via Distinct Mechanisms in Acute and Chronic Inflammation in NSCLC (ID 3034)

      S.M. Dubinett

      • Abstract

      Background:
      Dysregulated inflammation is associated with the development and progression of lung cancer. Pulmonary diseases characterized by increased inflammation, including emphysema and pulmonary fibrosis, are strongly related to heightened risk of lung cancer. Moreover, lung cancer patients with increased levels of inflammatory mediators or inflammatory cells have poor outcomes. It has been shown that dysregulated inflammatory cytokines in the tumor microenvironment can promote cancer metastasis. However, the mechanisms of this effect in lung cancer have not been fully understood. Interleukin 1β (IL-1β), a key pro-inflammatory cytokine, is associated with tumor aggressiveness and poor patient outcomes in NSCLC. Herein, we report that treatment of IL-1β leads to epithelial-to-mesenchymal transition (EMT) in NSCLC cell lines. Delineation of the underlying molecular pathway(s) may potentiate novel therapeutic strategies.

      Methods:
      We treated NSCLC cell lines with IL-1β acutely (3 days) and chronically (21 days) in vitro and identified EMT mediators using RNA interference and chemical inhibitors. Histone modifications and DNA methylation were analyzed with chemical inhibitors, ChIPassays and methylation-specific PCR. We utilized transwell migration, cell proliferation and anchorage-independent cell growth assays to evaluate the functional phenotypes

      Results:
      We found that following acute IL-1β exposure (within 7 days), the activator protein 1 (AP-1) transcription factor components, including Fra-1 and c-jun, mediate EMT. AP-1 functions downstream of ERK1/2 and JNK signaling and resides upstream of the transcription factors Slug and Zeb2. Importantly, inhibition of slug, zeb2, fra-1 or ERK1/2 and JNK signaling by RNA interference or chemical inhibitor is sufficient to abolish IL-1β-induced E-cadherin repression. This occurs concomitantly with decreased cell migration and invasion. Surprisingly, following prolonged IL-1β exposure (21 days), cells do not revert back to the epithelial state despite inhibition of these acute EMT mediators. We also found that following withdrawal of IL-1β after twenty one-day exposure, the treated cells are able to maintain their mesenchymal phenotype for more than 30 days before reverting back to an epithelial phenotype. We refer to this prolonged but reversible EMT program that persists in the absence of the original inflammatory stimulus as EMT “memory.” Further studies showed that fra-1 is only required to establish but not to maintain EMT memory. Chemical inhibition of a variety of enzymes involved in histone modifications and DNA methylation indicates the repression of E-cadherin is mediated by different mechanisms depending on the duration of IL-1β exposure. H3K27Me3 and histone acetylation mediate E-cadherin repression during acute EMT but DNA methylation is responsible for the downregulation of E-cadherin in EMT memory. In fact, we have found increased CpG island methylation in the E-cadherin promoter region in EMT memory. In vitro functional studies further showed that EMT memory enables cancer cells to enhance their motility but gradually regain proliferative advantage.

      Conclusion:
      We conclude that lung cancer cells utilize distinct mechanisms for EMT in response to acute and chronic inflammation. We also demonstrate that dynamic alteration of histone modification and DNA methylation can lead to prolonged but reversible EMT, subsequently creating a time window for cancer cells to migrate to distant organs and eventually undergo mesenchymal-epithelial transition to form macro-metastases.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-087 - A Phase I Study of Exemestane with Carboplatin and Pemetrexed in Postmenopausal Women with Metastatic, Non-Squamous Non-Small Cell Lung Cancer (ID 2171)

      S.M. Dubinett

      • Abstract
      • Slides

      Background:
      Lung cancer is the most common cause of cancer-related deaths in the US, with adenocarcinoma being the most common histologic subtype. Aromatase, a critical rate-limiting enzyme in estrogen biosynthesis, is notably expressed in NSCLC cells. Retrospective studies show that high NSCLC aromatase levels are associated with worse clinical outcome, particularly in postmenopausal women (Weinberg et al., Cancer Res, 2005; Mah et al., Cancer Res, 2007; Garon et al., J Thoracic Oncol, 2013). Estrogens are known survival factors in lung and promote expression of nucleotide excision repair enzyme ERCC1 that is implicated in resistance to platinum-therapy. In NSCLC cells, ERCC1 transcript expression is blocked by exemestane, an aromatase inhibitor (AI), enhancing cisplatin-induced apoptosis. In preclinical NSCLC xenograft models, exemestane exerts synergistic antitumor activity combined with cisplatin and results in prolonged tumor suppression (Marquez-Garban et al., Ann NY Acad Sci, 2009). These data provide a rationale to assess an AI in the clinic.

      Methods:
      Based on our preclinical studies, we are conducting a phase IB, open-label, single-center study in postmenopausal, treatment-naïve (except prior single-agent tyrosine kinase inhibitor use) women with metastatic, non-squamous NSCLC (NCT 01664754). We plan to enroll 12-15 participants divided into two dose-escalation cohorts of exemestane. All participants receive standard chemotherapy with pemetrexed (500 mg/m[2]) and carboplatin (AUC 6), both given intravenously every 3 weeks. Cohort 1, which added exemestane 25 mg orally daily, has completed enrollment without any dose-limiting toxicities. Cohort 2, for which enrollment started in December of 2013, evaluates exemestane at 50 mg orally daily. Our primary aim is to evaluate safety and tolerability of the indicated regimen. Secondary objectives are tumor response rate, quality of life, pharmacokinetics/pharmacodynamics, and correlative studies of biomarkers (such as blood estrogens, tumor ERs, aromatase, and apoptosis) with tumor response.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-063 - The Mutational Landscape of Pulmonary Premalignancy in the Context of Lung Adenocarcinoma (ID 1614)

      S.M. Dubinett

      • Abstract

      Background:
      While genomic alterations in lung cancer are being actively investigated, the early mutational events that occur within the pulmonary field of cancerization that subsequently drive early carcinogenesis are poorly understood. As a result, the clinical importance of premalignant lesions remains enigmatic. Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may progress to invasive cancer, however the mutational landscape that may predict progression has not been determined. In the present study we performed whole exome DNA sequencing to measure the incidence of somatic DNA alterations in matched sets of primary tumor, premalignant lesions and adjacent normal lung tissues.

      Methods:
      FFPE tissue blocks from 41 patients were obtained from the UCLA Lung Cancer SPORE Tissue Repository. The following regions were dissected from distal airways utilizing Laser Capture Microdissection: a) normal airway epithelial cells (1-3 regions), b) premalignant atypical adenomatous hyperplasia (AAH, 2-4 regions), c) adenocarcinoma in situ (AIS, 1-3 regions) and, d) adenocarcinoma (ADC, 1-3 regions). DNA was extracted and sequencing libraries were constructed followed by exome capture. Sequencing was performed on an Illumina HiSeq2000 with a mean coverage of ~50x per base.

      Results:
      Data analysis included analyses for germline and somatic variants, loss of heterozygosity and copy number alternations. Within each case, position-specific missense and nonsense mutations were compared. Different cases were compared for the mutations at a gene-specific level. Mutations found only in AAH lesions were defined as premalignant, in ADC as malignant, and in both AAH and ADC as progression-associated mutations. The analysis demonstrated that AAH lesions from the same patient often have different mutational profiles. We identified novel recurring progression-associated mutations in 33 genes, most of which have not been previously described as key drivers for lung cancer. Interestingly, recurring mutations were found in genes involved in calcium signaling and extracellular matrix/receptor interaction. The data was compared to the TCGA and COSMIC databases. Among affected proteins, only 3% overlapped with the COSMIC and approximately 6% with the TCGA database. Interestingly, all of the mutations overlapping with the COSMIC, were found to be common mutations in AAH. Furthermore, pathways affected by the mutated genes were identified utilizing Gene Ontology and pathways from the KEGG, Biocarta or Reactome databases. The observation that few genes mutated in both AAH and ADC are known as key drivers, indicates that: a) progression-associated mutations might facilitate malignant transformation by mutated key driver(s), or b) a combination of two or more progression-associated mutations that are not oncogenic alone, might drive malignant transformation. These hypotheses will be further tested by mapping progression- and malignant-associated genes in the context of pathways.

      Conclusion:
      Our data indicate that premalignant lesions from the same patient may have different mutational profiles. This inter-lesion heterogeneity suggests that a progression-associated mutational landscape could be defined in longitudinal studies of pulmonary premalignancy. These results could help identify targets for the development of targeted chemopreventive strategies for lung cancer. Supported by EDRN (U01CA152751-AS).

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    YIS - Young Investigator Session incl. Q & A with Longstanding IASLC Members (ID 238)

    • Event: WCLC 2015
    • Type: Young Investigator Session
    • Track: Other
    • Presentations: 1
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      YIS.03 - How to Write a Grant Application for Young Investigators (ID 3513)

      S.M. Dubinett

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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