10 research outputs found
Dependence of Tumor Cell Lines and Patient-Derived Tumors on the NAD Salvage Pathway Renders Them Sensitive to NAMPT Inhibition with GNE-618
Nicotinamide adenine dinucleotide (NAD) is a critical metabolite that is required for a range of cellular reactions. A key enzyme in the NAD salvage pathway is nicotinamide phosphoribosyl transferase (NAMPT), and here, we describe GNE-618, an NAMPT inhibitor that depletes NAD and induces cell death in vitro and in vivo. While cells proficient for nicotinic acid phosphoribosyl transferase (NAPRT1) can be protected from NAMPT inhibition as they convert nicotinic acid (NA) to NAD independent of the salvage pathway, this protection only occurs if NA is added before NAD depletion. We also demonstrate that tumor cells are unable to generate NAD by de novo synthesis as they lack expression of key enzymes in this pathway, thus providing a mechanistic rationale for the reliance of tumor cells on the NAD salvage pathway. Identifying tumors that are sensitive to NAMPT inhibition is one potential way to enhance the therapeutic effectiveness of an NAMPT inhibitor, and here, we show that NAMPT, but not NAPRT1, mRNA and protein levels inversely correlate with sensitivity to GNE-618 across a panel of 53 non-small cell lung carcinoma cell lines. Finally, we demonstrate that GNE-618 reduced tumor growth in a patient-derived model, which is thought to more closely represent heterogeneous primary patient tumors. Thus, we show that dependence of tumor cells on the NAD salvage pathway renders them sensitive to GNE-618 in vitro and in vivo, and our data support further evaluation of the use of NAMPT mRNA and protein levels as predictors of overall sensitivity
Interactions between MUC1 and p120 Catenin Regulate Dynamic Features of Cell Adhesion, Motility, and Metastasis
Transcriptional Subtypes Resolve Tumor Heterogeneity and Identify Vulnerabilities to MEK Inhibition in Lung Adenocarcinoma
Cyclin-Dependent Kinase 5 Is Amplified and Overexpressed in Pancreatic Cancer and Activated by Mutant K-Ras
Dependence of Tumor Cell Lines and Patient-Derived Tumors on the NAD Salvage Pathway Renders Them Sensitive to NAMPT Inhibition with GNE-618
An Anti-B7-H4 Antibody–Drug Conjugate for the Treatment of Breast Cancer
B7-H4
has been implicated in cancers of the female reproductive system and
investigated for its possible use as a biomarker for cancer, but there
are no preclinical studies to demonstrate that B7-H4 is a molecular
target for therapeutic intervention of cancer. We provide evidence
that the prevalence and expression levels of B7-H4 are high in different
subtypes of breast cancer and that only a few normal tissues express
B7-H4 on the cell membrane. These profiles of low normal expression
and upregulation in cancer provide an opportunity for the use of antibody–drug
conjugates (ADCs), cytotoxic drugs chemically linked to antibodies,
for the treatment of B7-H4 positive cancers. We have developed an
ADC specific to B7-H4 that uses a linker drug consisting of a potent
antimitotic, monomethyl auristatin E (MMAE), linked to engineered
cysteines (THIOMAB) via a protease labile linker. We will refer to
ADCs that use the THIOMAB format as TDCs to help distinguish the
format from standard MC-vc-MMAE ADCs that are conjugated to the interchain
disulfide bonds. Anti-B7-H4 (h1D11)-MC-vc-PAB-MMAE (h1D11 TDC) produced
durable tumor regression in cell line and patient-derived xenograft
models of triple-negative breast cancer. It also binds rat B7-H4 with
similar affinity to human and allowed us to test for target dependent
toxicity in rats. We found that our anti-B7-H4 TDC has toxicity findings
similar to untargeted TDC. Our results validate B7-H4 as an ADC target
for breast cancer and support the possible use of this TDC in the
treatment of B7-H4<sup>+</sup> breast cancer