Targeting hTERT/telomerase for managing acquired resistance to third generation EGFR-TKIs in lung cancer

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.