Author of

• 16549

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  P1.02 - Poster Session with Presenters Present (ID 454)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 16604

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    P1.02-055 - Synthetic Lethality Dictates the Mutual Exclusivity of Oncogenic Mutations in Lung Adenocarcinoma (ID 6190)

    14:30 - 14:30  |  Author(s): A. Unni
    • Abstract

    Background:
    EGFR mutations are present in ~15% and KRAS mutations in ~30% of lung adenocarcinomas (LACs). Yet, as several observers have noted, no individual LAC appears to carry mutations in both, even in the setting of resistance to EGFR kinase inhibitors. The typical explanation given is that the two genes are entirely functionally redundant, thereby eliminating any selective advantage to mutation of both. In this study we tested an alternative hypothesis for this mutual exclusivity: that co-occurrence of mutations in both KRAS and EGFR is deleterious to the evolving cancer cell. Furthermore, we aimed to characterize the specific cellular effects and signalling pathways induced by mutant KRAS and EGFR co-induction and determine whether this information could be used to design new strategies to inhibit LACs.
    
    Methods:
    Next-generation sequence data for over 600 human LACs were acquired from public sources and analyzed for co-incidence of KRAS and EGFR mutation and the relationship to smoking status. Transgenic mice that express both mutant oncogenes specifically in the lung epithelium were generated to test the effects on LAC development. LAC cell lines with endogenous mutations in either KRAS or EGFR were engineered with lentiviral vectors to conditionally express the second oncogene and assessed for cell viability, gene expression and protein phosphorylation changes. Temporal phosphoproteome assessment of cells co-expressing both oncogenes is currently ongoing to determine the specific signalling pathways affected.
    
    Results:
    We confirmed the mutual exclusivity of KRAS and EGFR mutations and demonstrated that this relationship is not due to limited power to detect concurrent mutations in either smokers or non-smokers. While no effect on tumor latency was observed in transgenic mice that express both mutant oncogenes, the resulting tumors preferentially expressed only one of the two transgenic oncogenes, indicating negative selection against co-expression. Introduction of the second oncogene into LAC cells expressing either mutant KRAS or EGFR stimulated the loss of cell viability. The most prominent features accompanying loss of cell viability were vacuolization, other changes in cell morphology, and increased macropinocytosis. Activation of ERK, p38 and JNK was observed in cells expressing both mutants suggesting that an overly active MAPK signaling pathway may mediate this synthetic lethal phenotype. Lastly, this effect is dependent on functionally active EGFR, since inhibition of the EGFR tyrosine kinase with erlotinib rescued cells from the detrimental effects of co-expression.
    
    Conclusion:
    Together, our findings indicate that mutual exclusivity of oncogenic mutations may reveal unexpected vulnerabilities and therapeutic possibilities.