Abstract
Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive “active-site” mTOR inhibitors produce more complete mTOR inhibition and are more effective than rapamycin in preclinical models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials of active-site mTOR inhibitors, it will be important to identify resistance mechanisms that might limit drug efficacy in certain patients. From a panel of diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is particularly resistant to apoptosis in the presence of active-site mTOR inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic initiation factor 4E-binding protein-1 (4EBP1), a key negative regulator of translation controlled by mTOR. Although VAL cells express the related protein 4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with active-site mTOR inhibitors. These findings provide a naturally occurring example of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR inhibitors.
Highlights
In order to maintain rapid proliferation and survival, cancer cells depend on high rates of protein synthesis and on selective translation of cap-dependent mRNAs encoding cell cycle regulators and anti-apoptotic proteins [1,2]
Previous work in our lab established the efficacy of Active-site mTOR inhibitors (asTORi) in models of pre-B acute lymphoblastic leukemia and demonstrated reduced hematotoxicity and immunosuppression compared to rapamycin or dual PI3K/mechanistic target of rapamycin (mTOR) inhibitors [18,19]
In this study we have identified a human Diffuse large B-cell lymphoma (DLBCL) line whose resistance to asTORi can be attributed in part to a low ratio of 4EBP/Eukaryotic initiation factor 4E (eIF4E) expression
Summary
In order to maintain rapid proliferation and survival, cancer cells depend on high rates of protein synthesis and on selective translation of cap-dependent mRNAs encoding cell cycle regulators and anti-apoptotic proteins [1,2]. Eukaryotic initiation factor 4E (eIF4E), which together with eukaryotic initiation factor 4G (eIF4G) and eukaryotic initiation factor 4A (eIF4A) form the capbinding complex, is frequently overexpressed in human cancer and can cooperate with the Myc oncogene in an experimental lymphoma model [3]. A key upstream regulator of eIF4E is the serine/threonine kinase mTOR [5,6,7]. The mTOR enzyme forms two complexes, TORC1 and TORC2, which are independently regulated and have distinct substrates. One set of important TORC1 substrates are the eIF4E-binding proteins (4EBPs), 4EBP1 and 4EBP2 [9]. When dephosphorylated, these proteins suppress cap-dependent translation by sequestering eIF4E. TORC1 phosphorylates 4EBPs to relieve eIF4E inhibition and promote cap-dependent translation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
