Targeting N-myristoylation for therapy of B-cell lymphomas

Abstract

Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.

N-myristoyltransferase inhibition is synthetic lethal in MYC-deregulated cancers

“…A recent report has proposed that the cytotoxicity of NMTi in B cell lymphomas arises from impaired B cell receptor (BCR) signaling through Src-family kinase (SFK) SRC and LYN degradation, both known NMT substrates (12). We tested this hypothesis through gene-effect score correlation analysis between SFK and NMT1 gene knockout across cancer cell lines or specifically in leukemias and lymphomas ( Supplementary Fig.…”

“…NMT has previously been proposed as a target in cancer (10), but a rationale supporting a therapeutic index for NMT inhibition (NMTi) is yet to be identified. Many prior studies have been limited by availability of potent and selective NMT inhibitors (11), and focused on individual NMT substrates (12) rather than addressing the system-wide consequences of NMTi across multiple cellular pathways, and its interactions with dynamic protein turnover. Recent discovery of the first potent and selective dual NMT1/NMT2 inhibitors provides a new avenue to address pharmacological validation of NMT as a target in cancer (13), and we hypothesized that increased dependency on NMT could arise at the system level from deregulation of specific oncogenes.…”

Protein Lipidation by Palmitoylation and Myristoylation in Cancer

“…PCLX-001 is reported to possess a greater inhibitory effect in hematological malignancies but less so in solid tumor cell lines. The proposed mechanism of PCLX-001 on tumors is apoptotic cell death through the attenuation of Src myristoylation, basal Src levels, and downstream survival signaling of B-cell receptor ( Beauchamp et al, 2020 ). Other than B-cell lymphoma, PCLX-001 has been reported to effectively kill several breast cancer cell line subtypes ranging from breast carcinoma, ductal carcinoma, and breast adenocarcinoma in both in vitro and in vivo models ( Mackey et al, 2021 ).…”

N-myristoyltransferase proteins in breast cancer: prognostic relevance and validation as a new drug target

“…We found that NMT1 protein levels correlated with poor prognosis in general and that NMT2 protein could not be detected in the majority of breast cancer samples and when it was detected it was linked with a poorer prognosis. While NMTs have been proposed to be potential anti-cancer targets, herein we demonstrate the potent pan-NMT inhibitor PCLX-001 [ 10 – 12 ] can efficiently target breast cancer by reducing the viability of numerous breast cancer cell lines in vitro and cause disease regression in vivo in an established murine xenograft breast cancer model.…”