SUMMARY
The ability of cancer cells to acquire resistance to anticancer drugs, resulting in eventual treatment failure, is
one of the most challenging problems in cancer therapy. Osimertinib (AZD89291), an EGFR mutation-selective
EGFR tyrosine kinase inhibitor (EGFR-TKI), is FDA-approved for patients with EGFR mutant (EGFRm) NSCLC
that has become resistant to 1st generation EGFR-TKIs via T790M mutation and for EGFR mutation-positive
advanced NSCLC as front-line treatment. Despite promising clinical efficacy, acquired resistance inevitably
occurs to osimertinib, limiting its long-term clinical benefit. Thus, a thorough understanding of molecular
mechanisms accounting for the emergence of acquired resistance to osimertinib and other 3rd generation
EGFR-TKIs and the development of effective strategies to manage acquired resistance is an urgent and critical
area of unmet need in the clinic. Telomere maintenance via telomerase reactivation is directly linked to
uncontrolled cell growth and thus is a hallmark of cancer cells. While telomerase activity is silenced in most
human adult somatic or well-differentiated cells, it is reactivated in up to 90% of tumors. Thus, telomerase
represents an attractive target for highly selective cancer therapeutics. Intriguingly, we found that osimertinib-
treated human EGFRm NSCLC cell lines possess substantially reduced mRNA and protein levels of human
TERT (hTERT), a catalytic protein subunit of telomerase complex that determines its activity. In EGFRm
NSCLC cell lines with osimertinib acquired resistance, basal hTERT levels were elevated compared with their
parental cell lines and became insensitive to osimertinib modulation. hTERT elevation was also detected in the
majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment. Knockdown of hTERT or chemical
inhibition of telomerase sensitized osimertinib-resistant cells to osimertinib. These preliminary data suggest a
critical role of hTERT/telomerase in modulating the responses of EGFRm NSCLC cells or tumors to osimertinib
or other 3rd generation EGFR-TKIs. Thus, we hypothesize that effective suppression of hTERT/telomerase is a
critical event in maintaining long-term therapeutic efficacy of osimertinib or other 3rd generation EGFR-TKIs in
the treatment of EGFRm NSCLCs. This hypothesis will be tested by accomplishing the following three aims: 1)
To understand the molecular mechanisms by which osimertinib suppresses hTERT expression in EGFRm
NSCLC cells; 2) To demonstrate the biological significance of hTERT/telomerase modulation in regulating the
responses of EGFRm NSCLC cells to osimertinib including development of acquired resistance; and 3) To
develop efficacious strategies for managing (delaying and overcoming) acquired resistance to osimertinib by
targeting hTERT/telomerase. The objectives of this proposal are to fully understand the mechanisms by which
osimertinib inhibits hTERT expression and telomerase activity, to demonstrate its critical role in mediating cell
response to osimertinib and other 3rd generation EGFR-TKIs including the acquired resistance, and to develop
effective therapeutic strategies to manage osimertinib acquired resistance by targeting hTERT/telomerase.