A Novel Strategy to Inhibit Drug-Resistant Non-Small Cell Lung Cancer Cells

Reardon, Madeleine, Vino Cheriyan, and Arun Rishi

 

Non-small cell lung cancers (NSCLC) account for 85% of all lung

cancers and are a very heterogeneous disease. Despite

development of number of therapies, the prognosis remains poor

due in part to emergence of resistant disease. CARP-1 Functional

Mimetic (CFM) compounds bind with CARP-1, stimulate CARP-1

expression, and apoptosis. Here we tested whether CFM analog

4.16 inhibits growth of NSCLC cells that express mutant Epidermal

Growth Factor Receptor (EGFR) Tyrosine Kinase (RTK), and the

tyrosine kinase inhibitor (TKI)-resistant NSCLC cells. We utilized

NSCLC H1975 cells that harbor T790M mutation in the EGFR and

are resistant to first and second generation TKIs such as Gefitinib

and Erlotinib, while are responsive to the third generation TKI

Rociletinib. We next generated multiple, independent sublines of

H1975 cells that were grown in chronic presence of Rociletinib.

MTT-based cell viability assays established resistance of H1975

sublines to Rociletinib, and Western blots indicated elevated wild

type EGFR. On this basis, we tested the ability of TKI Gefitinib that

targets wild type EGFR as a single agent as well as in combination

with CFM 4.16 to inhibit Rociletinib-resistant NSCLC cells. Our data

revealed that although CFM-4.16 or Gefitinib inhibited growth of

Rociletinib-resistant cells, their growth inhibition by a combination

of both the agents was similar to that noted for the cells that were

treated with CFM-4.16 alone. Therefore, our preliminary findings

suggest CFM 4.16 alone or in combination with TKIs could be a

suitable strategy to inhibit resistant NSCLCs with mutant EGFRs.