A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor

Abstract

The PI3K–AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.

Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment

“…A number of these agents, e.g., trametinib and its combination with palbociclib, have been used or are under investigation for treatment of NSCLC [ 79 , 80 ]. PD-0325901 has an in vitro inhibiting effect in NSCLC; however, a phase II clinical trial of that antitumor agent in NSCLC patients did not meet the primary efficacy end point [ 81 , 82 ]. RDEA119 (refametinib) has antitumor activity in a variety of cancer types including in vitro activity in NCSLC, and it has been under evaluation for its effectiveness in NSCLC [ 82 – 84 ].…”

Targeting MDK Abrogates IFN-γ-Elicited Metastasis inCancers of Various Origins

“…iMDK decreased cell viability of the MDK-positive cancer cells in a dose-dependent manner, but less affected the MDK-negative cancer and non-transformed cells ( 36 ). The inhibitory effect of iMDK on cancer malignant behaviors has been validated in oral squamous cell carcinoma ( 37 ), non-small cell lung cancer ( 36 , 38 ), and prostate cancer ( 39 ). Importantly, systemic administration of iMDK in mouse didn’t cause obvious systemic toxicity ( 36 ), highlighting a high safety for potential clinical use.…”

Dual targeting of MEK and PI3K effectively controls the proliferation of human EGFR-TKI resistant non-small cell lung carcinoma cell lines with different genetic backgrounds

“…In the case of acquired EGFR-TKI resistance, common mechanisms include the emergence of an EGFR gatekeeper mutation (T790M) and MET gene amplification [ 7 , 8 ]. In addition, PIK3CA mutations can contribute toward EGFR-TKIs resistance in a subpopulation of NSCLC tumors [ 9 ]. However, in either primary or acquired resistance, the downstream pathways involving RAS/RAF/MAP kinase-ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway and the PI3K/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway are constitutively activated.…”