Using the Mcl-1-binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of lung cancer <i>in vitro</i> and <i>in vivo</i>.
Thus, nicotine-induced cell survival and chemoresistance may occur in a mechanism by stimulating Mcl-1 phosphorylation and its interaction with Bak, which may contribute to improving the efficacy of chemotherapy in the treatment of human lung cancer.
Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors.
Caenepeel and colleagues and Ramsey and colleagues have developed two novel, potent, and selective MCL1 inhibitors that are effective against many hematologic malignancies, and Nangia and colleagues describe how one of these inhibitors can be successfully combined with BCL-xL and MEK inhibition to treat KRAS-mutated lung cancer.<i>See related article by Ramsey et al., p. 1566</i>.<i>See related article by Caenepeel et al., p. 1582</i>.<i>See related article by Nangia et al., p. 1598</i>.
Therefore, our study suggests that the protein stability of Mcl-1 is governed by FBXO4, which plays an important role in cell survival and chemotherapy for lung cancer.
These studies suggest that simultaneous blocking of ATM/Mcl-1 molcules or downstream Erk signaling may recover the cisplatin-resistance of lung cancer.
Lung cancer models stably expressing BCL-xL or MCL-1 were irradiated to study cell death, clonogenic survival, and DNA repair kinetics in vitro, and growth suppression of established tumors in vivo.
In the present study, we acidized the medium with 2-(N-morpholino)-ethanesulfonic acid (MES monohydrate) to mimic the acidic tumor microenvironment and observed the effects of acidification on lung cancer cell viability, the expression of ATP-binding cassette sub-family G member 2 (ABCG2) and myeloid cell leukemia‑1 (Mcl-1), and activation of the PI3K-Akt pathway.
Thus, these findings provided that in lung cancer cells, tumor suppressor miR-451 enhanced DPP sensitivity via regulation of Mcl-1 expression, which could be served as a novel therapeutic target for the treatment of chemotherapy resistant in lung cancer.
The TWEAK-Fn14 signaling axis enhances lung cancer cell survival and therapeutic resistance through Mcl-1, positioning both TWEAK-Fn14 and Mcl-1 as therapeutic opportunities in lung cancer.
Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: implications for context-dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor.
The most potent compound BI79D10 binds to Bcl-XL, Bcl-2, and Mcl-1 with IC50 values of 190, 360, and 520 nmol/L, respectively, and potently inhibits cell growth in the H460 human lung cancer cell line with an EC50 value of 680 nmol/L, expressing high levels of Bcl-2.
Taken together, these results identify c-FLIP(L) and Mcl-1(L) as the major determinants of acquired TRAIL resistance and could be molecular targets for improving the therapeutic value of TRAIL against lung cancer.