<p>Lung cancer
is the third most prevalent cancer in the world; however it is the leading
cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC)
accounts for ~85% of the lung cancer cases. The current strategies to treat
NSCLC patients with frequent causal genetic mutations is through targeted
therapeutics. Approximately 10-35% of NSCLC patient tumors have activated
mutations in the Epidermal Growth Factor Receptor (EGFR) resulting in
uncontrolled cellular proliferation. The standard-of care for such patients is
EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs), a class of targeted therapeutics
that specifically inhibit EGFR activity. One such EGFR-TKI used in this study
is erlotinib. Following erlotinib treatment, tumors rapidly regress at first;
however, over 50% of patients develop erlotinib resistance within a year post
treatment. Development of resistance remains to be the major challenge in
treatment of NSCLC using EGFR-TKIs such as erlotinib. </p>
<p>In
approximately 60% of cases, acquired erlotinib resistance in patients is
attributed to a secondary mutation in EGFR, whereas in about 20% of cases,
activation of alternative signaling pathways is the reported mechanism. For the
remaining 15-20% of <a>cases</a> the mechanism of
resistance remains unknown. Therefore, it can be speculated that the common
methods used to identify genetic mutations in tumors post erlotinib treatment,
such as histologic
analysis and genetic screening may fail to identify alterations in epigenetic
mediators of erlotinib resistance, also including microRNAs (miRNAs). MiRNAs
are short non-coding RNAs that post-transcriptionally negatively regulate their
target transcripts. Hence, in this study two comprehensive screens were
simultaneously conducted in erlotinib sensitive cells: 1) a genome-wide
knock-out screen, conducted with the hypothesis that loss of function of
certain genes drive erlotinib resistance, 2) a miRNA overexpression screen,
conducted with the hypothesis that certain miRNAs drive the development of
erlotinib resistance when overexpressed. The overreaching goal of the study was
to identify novel drivers of erlotinib resistance such as microRNAs or other
epigenetic factors in NSCLC.</p><p>The findings of this study led to the identification of a
tumor suppressive protein and an epigenetic regulator, SUV420H2 (KMT5C) that
has never been reported to be involved in erlotinib resistance. On the other
hand, the miRNA overexpression screen identified five miRNAs that contribute to
erlotinib resistance that were extensively analyzed using multiple
bioinformatic tools. It was predicted that the miRNAs mediate erlotinib
resistance via multiple pathways, owing to the ability of each miRNA to target multiple
transcripts via partial complementarity. Importantly, a correlation between the
two screens was identified clearly supporting the use of two simultaneous
screens as a reliable technique to determine highly significant miRNA-target
interactions. Overall, the findings from this study suggest that epigenetic
factors, such as histone modifiers and miRNAs function as critical mediators of
erlotinib resistance, possibly belonging to the 15-20% of NSCLC cases with
unidentified mechanisms involved in erlotinib resistance.</p><p></p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12032139 |
| Date | 16 April 2020 |
| Creators | Arpita S Pal (8612079) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Identification_of_novel_epigenetic_mediators_of_erlotinib_resistance_in_non-small_cell_lung_cancer/12032139 |
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