Inhibition of Acetyl-CoA Carboxylase Induces Endoplasmic Reticulum Stress and Augments the Efficacy of Anticancer Therapies
Shan and colleagues’ 2026 study, with senior author Lajos Pusztai, extends the preclinical rationale for ACC inhibition.
Researchers investigated the ACC inhibitor PF-05175157 in cancer cells and mouse xenografts, reporting lipid changes, endoplasmic reticulum stress, and anticancer activity, including in some models resistant to targeted therapies.
The study at a glance
- Human cancer cell lines in the single-agent screen
- 385
- FDA-approved anticancer drugs in the combination screen
- 166
- Breast-cancer cell lines in the combination screen
- 10
- Combination partners evaluated in mice
- 3
These numbers describe the study design. They are not counts of effective treatments, separate animal studies, or clinical trials.
What the combination experiments showed
The combination screen evaluated 166 FDA-approved anticancer drugs across 10 breast-cancer cell lines. The researchers then evaluated three partner therapies in mouse xenografts: doxorubicin and vinorelbine, both chemotherapies, and fulvestrant, an endocrine therapy.
- Doxorubicin: adding the ACC inhibitor inhibited tumor growth more than either treatment alone in the MDA-MB-468 model (Figure 4C).
- Vinorelbine: combinations showed enhanced antitumor activity in the MDA-MB-468 model, with tumor regression and some complete responses at the higher tested dose (Figure 4D).
- Fulvestrant: both fulvestrant alone and the combination inhibited tumor growth versus vehicle in the HCC1500 model. This comparison does not establish that the combination was superior to fulvestrant alone (Supplementary Figure S11).
Evidence in treatment-resistant models
The study included breast-cancer cells resistant to endocrine therapy, the CDK4/6 inhibitor palbociclib, or the HER2-targeted therapy trastuzumab.
In a separate mouse experiment using fulvestrant-resistant MCF7/FR tumors, the ACC inhibitor alone inhibited tumor growth and improved survival compared with the fulvestrant-treated control group. This was a single-agent experiment in a resistant model, not an additional combination study (Supplementary Figures S12–S13).
Study details: Shan et al., Clinical Cancer Research, 2026, results and Figure 4C–D; Supplementary Figures S11–S13. Read the publication and supporting material.
Relevance to our program
The findings inform NMG’s biological rationale and future study design. A distinct metabolic mechanism also creates questions about potential combinations with existing anticancer therapies.
The published combination findings concern the studied ACC inhibitor, not NMG’s formulated product. They do not establish clinical benefit or validate an NMG combination regimen. NMG’s formulation would require its own combination, exposure, and tolerability studies.