Non-small cell lung cancer (NSCLC) makes up the majority of lung cancers,
which remains the leading cause of cancer mortality worldwide. NSCLC with mutant
epidermal growth factor receptor (EGFR) is currently treated with tyrosine kinase
inhibitors (TKIs). TKIs have proven effective in improving survival until resistance is
conferred, mostly by way of the exon 20, threonine 790 to methionine (T790M) point
mutation in EGFR. The mechanism by which this point mutation arises is poorly
understood. Herein we report a possible pathway by which the C to T transition that leads
to T790M comes about. We show that activation-induced cytidine deaminase (AID)
mRNA expression is induced upon treatment with EGFR TKIs in mutant-EGFR human
lung cancer cell lines but not in control cell lines. We also show that stable expression of
AID is sufficient to produce resistance to one such TKI, erlotinib, and is sufficient to
produce T790M itself. We also report that B-cell lymphoma 6 (BCL6) may precede AID
in this pathway. Our results show that BCL6 is upregulated in these cell lines treated with
EGFR TKIs but not in normal bronchial cells. We then treated human lung cancer cell
lines with EGFR TKIs in combination with BCL6 inhibitors. Our results show that AID
is dependent upon BCL6 expression. Finally, we report on results from a transient BCL6
overexpression which lead us to believe that AID mRNA receives input from at least one
alternate pathway in addition to BCL6. We also performed these experiments on a family
of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)
cytidine deaminases, that show they may be involved in this pathway downstream of
AID. Taken together, our results suggest a potential pathway involving BCL6, AID, and
APOBEC cytidine deaminases that lead to the C to T transition that produces T790M,
thereby conferring resistance to EGFR TKIs in mutant-EGFR NSCLC. They also provide
potential new targets for treatment should further study confirm our results. / 2021-10-07T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/38589 |
| Date | 07 October 2019 |
| Creators | Gergis, Carol |
| Contributors | Kobayashi, Susumu, McKnight, C. James |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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