Abstract
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 GI50 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 GI50 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.
Highlights
Lung carcinoma is the leading cause of cancer death in the United States but worldwide [1,2]
We have previously reported that CARP-1 functional mimetic (CFM) compounds possess anti-cancer properties [9, 17,18,19,20], and we further observed that the CFM-4.16 analog effectively inhibited the growth of parental as well as drug resistant Renal cell carcinoma (RCC), and human and murine triple negative breast cancer (TNBC) cells in vitro and in vivo. [21, 22]
Given that development of drug-resistant non-small cell carcinoma (NSCLC) remain a formidable problem that contributes to treatment failure and poor prognosis [2,3,4,5,6], we tested whether CFMs, in particular CFM-4.16, would inhibit parental and drug-resistant NSCLC cells
Summary
Lung carcinoma is the leading cause of cancer death in the United States but worldwide [1,2]. A significant subset of NSCLCs harbor classical activating mutation in the kinase domain of the EGFR [2, 4] This deletion of EGFR exon 19 (Δ19) is associated with good clinical responses to first generation EGFR TKIs such as Gefitinib or Erlotinib [2, 4]. A vast majority of patients develop resistance to these TKIs due in part to activation and/or expression of alternate, redundant RTKs as well as emergence of the “gatekeeper” T790M mutation in the kinase domain of EGFR. This EGFR T790M mutation leads to resistance to most clinically available first and second generation EGFR TKIs by increasing the affinity of the receptor to adenosine triphosphate (ATP). There is an urgent need to identify and devise new approaches to treat NSCLCs and their TKIresistant phenotypes
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