Non-small cell
lung cancers (NSCLC) account for 85% of all
lung cancers, and the
epidermal growth factor receptor (EGFR) is highly expressed or activated in many NSCLC that permit use of EGFR
tyrosine kinase inhibitors (TKIs) as frontline
therapies. Resistance to EGFR TKIs eventually develops that necessitates development of improved and effective
therapeutics. CARP-1/CCAR1 is an effector of apoptosis by
Doxorubicin,
Etoposide, or
Gefitinib, while CARP-1 functional mimetic (CFM) compounds bind with CARP-1, and stimulate CARP-1 expression and apoptosis. To test whether CFMs would inhibit TKI-resistant NSCLCs, we first generated and characterized TKI-resistant NSCLC cells. The GI 50 dose of
Erlotinib for parental and
Erlotinib-resistant HCC827 cells was ∼0.1 μM and ≥15 μM, respectively. While
Rociletinib or Ocimertinib inhibited the parental H1975 cells with GI 50 doses of ≤0.18 μM, the Ocimertinib-resistant pools of H1975 cells had a GI50 dose of ∼12 μM. The GI50 dose for
Rociletinib-resistant H1975 sublines ranged from 4.5-8.0 μM. CFM-4 and its novel analog CFM-4.16 attenuated growth of the parental and TKI-resistant NSCLC cells. CFMs activated p38/JNKs, inhibited oncogenic cMet and Akt
kinases, while CARP-1 depletion blocked NSCLC cell growth inhibition by CFM-4.16 or
Erlotinib. CFM-4.16 was synergistic with B-Raf-targeting in NSCLC,
triple-negative breast cancer, and
renal cancer cells. A nano-
lipid formulation (NLF) of CFM-4.16 in combination with
Sorafenib elicited a superior growth inhibition of xenografted
tumors derived from
Rociletinib-resistant H1975 NSCLC cells in part by stimulating CARP-1 and apoptosis. These findings support therapeutic potential of CFM-4.16 together with B-Raf targeting in treatment of TKI-resistant NSCLCs.