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E.E. Vokes
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ORAL 36 - Translational Science/Radiation (ID 151)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:E. Vokes, B. Kavanagh
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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ORAL36.03 - Discussant for ORAL36.01, ORAL36.02 (ID 3566)
16:45 - 18:15 | Author(s): E.E. Vokes
- Abstract
- Presentation
Abstract not provided
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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
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-001 - MET/RON Inhibition in KRAS Mutated Non Small Cell Lung Cancer (ID 2174)
09:30 - 17:00 | Author(s): E.E. Vokes
- Abstract
Background:
Molecular genetics have allowed us to categorize non-small cell lung cancer (NSCLC) based on their genetic profile. KRAS mutations occur in 25-30% of NSCLCs. KRAS regulates cellular function in response to growth factors and their receptors. When mutated, KRAS is constitutively active and is responsible for driving tumor oncogenesis. Direct inhibition of KRAS has not been a successful clinical strategy. The strategy of synthetic lethality (targeting a non-lethal defect in cancer cells combined with a second defect, that together make the cancer cell more susceptible to treatment) has gained traction in recent years. Several synthetic lethal targets have been identified with KRAS. We have previously shown that MET plays an important role in the oncogenic addiction observed in KRAS mutated NSCLC and contributes to both tumor growth and metastasis. However, the development of resistance in MET targeting due to upregulation of RON, a related receptor tyrosine kinase, is also evident. Our hypothesis is that dual targeting of MET and RON may be synthetic lethal to KRAS mutated NSCLC and studies to investigate this as a potential therapeutic strategy are warranted.
Methods:
MET- and RON-specific siRNAs (small molecule inhibitors), crizotinib, and the ligand for MET (hepatocyte growth factor), were used in in vitro assays. Immunoblotting, cell viability, and cell migration assays were carried out in a panel of KRAS mutated as well as KRAS wild type NSCLC cells. In addition, human bronchial epithelial cells (HBECs) that were rendered tumorigenic with sequential mutations in CDk4, hTERT, p53, and KRAS genes were also used.
Results:
Our analysis of a panel of NSCLC cells showed that most KRAS mutant cell lines express both MET and RON, and stimulation with HGF activated KRAS effector pathways such as MAPK, AKT and S6RP. When we silenced MET expression with siRNA, it led to upregulation of RON, indicating the interaction between MET and RON. Cell viability assays using crizotinib showed that KRAS mutant cell lines (A549 and H460) are three-fold more sensitive than KRAS wild type cells (H1975 and H1437), and cells with MET amplification (H1993) showed the highest response. Preliminary data with the KRAS-transformed HBECs also showed that they are more sensitive to crizotinib inhibition than the non-transformed control HBECs. Wound healing assays with these same cells showed a similar trend in MET specific inhibition of cell migration in KRAS-mutated cells compared to wild type cells.
Conclusion:
These data highlight the potential therapeutic benefit of targeting MET and RON simultaneously in a subpopulation of KRAS mutated NSCLC patients who may have MET overexpression or amplification. Based on KRAS oncogenic addiction to MET, we propose that NSCLC cells that are MET amplified and KRAS mutated are potentially synthetic lethal and will benefit from dual MET/RON treatment
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-037 - Genomic Alterations of KRAS, EGFR, and ALK in Patients with Non-Small Cell Lung Cancer, Single Institution Experience (ID 1722)
09:30 - 17:00 | Author(s): E.E. Vokes
- Abstract
Background:
This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. This study reviews the results of extensive genetic analysis in non-small cell lung cancer (NSCLC) patients from a University of Chicago database in order to: describe how actionable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially actionable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS.
Methods:
Thoracic Oncology Research Program (TORP) Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. Three hundred and sixty four patients included in this analysis had advanced NSCLC and underwent genotype testing by FoundationOne, Caris Molecular Intelligence, and Response Genetics.
Results:
99.4% (159/160) of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor types. However, mutations were not mutually exclusive. For the entire cohort 28% of patients were African Americans; adenocarcinoma was the most commonly tested tumor subtype; 91% of KRAS mutations were detected in smokers; 46% of EGFR alterations and 50% of ALK translocations were detected in never smokers. The majority of ALK translocations were detected in adenocarcinomas.
Conclusion:
Personalized medicine is a significant step forward in the realm of lung cancer treatment. In conjunction with NGS to identify and characterize tumor specific molecular abnormalities, biomarker-driven therapies have improved patients’ overall survival. NGS in this study identified potentially actionable genetic alterations across various tumor histology subtypes, races and smoking status. NGS also provided additional information by uncovering targetable concurrent alterations or alterations of unknown significance at this point in time, but potentially targetable in the future.
