Molecular Pathway Figure

FBXW7, Biotin & c-MYC: The Glutamine Bypass Mechanism

How the tumor suppressor FBXW7 and the vitamin biotin together control whether a cancer cell can escape glutamine addiction. Based on Lisci et al., Molecular Cell 2026.

Tumor Suppressor
Oncogene / Cancer Driver
Transcriptional Repressors
Enzyme
Metabolite
Vitamin / Cofactor
Mitochondria (TCA Cycle)
Nucleus
Panel A — FBXW7 Functional Metabolic Flexibility ✓
CYTOPLASM NUCLEUS — NUCLEAR ZONE — PC Gene Promoter 🟢 OPEN — Active ★ Inside Nucleus mRNA MITOCHONDRIA TCA Cycle → ATP · Biosynthesis ★ Inside Mitochondria FBXW7 Tumor Suppressor c-MYC ⬇ Degraded Ub tags Ub Ub Proteasome ♻️ Degrades → destroyed c-MYC kept low → PC gene stays ON Pyruvate Carboxylase (PC) ✓ Expressed & Active Translated 🟣 Biotin Vitamin B7 · Cofactor activates ✓ Pyruvate from glycolysis Oxaloacetate (OAA) · TCA entry Pyruvate → OAA enters TCA ✅ Can Bypass Glutamine Metabolically Flexible Cell
Panel B — FBXW7 Mutated / Lost Glutamine Addiction ✗
CYTOPLASM NUCLEUS — NUCLEAR ZONE — ★ Repressor Complex (Nuclear) MAX MNT SIN3A PC Gene Promoter 🔴 SILENCED ★ Inside Nucleus ⛔ No mRNA MITOCHONDRIA TCA Cycle → ATP · Biosynthesis ★ Inside Mitochondria FBXW7 ❌ Mutated / Lost c-MYC ⬆ Accumulates Not degraded! ✗ no Ub Recruits repressors to PC promoter Pyruvate Carboxylase (PC) ❌ Not Expressed 🟣 Biotin ⛔ No PC to activate Pyruvate ⛔ Can't enter TCA Glutamine ⬆ ONLY fuel source GLS → α-KG → TCA GLS enzyme α-KG → TCA ONLY ROUTE to TCA ❌ Trapped: Glutamine Addiction Vulnerable to Glutamine Starvation

🔬 Step-by-Step: How FBXW7 Loss Causes Glutamine Addiction

1

FBXW7 mutation: The tumor suppressor gene FBXW7 is lost or mutated — one of the most common tumor suppressor mutations in human cancers (colorectal, T-cell leukemia, cholangiocarcinoma, and others).

2

c-MYC accumulates: Without FBXW7, the oncogene c-MYC is no longer tagged for destruction by the proteasome. It builds up inside the cell to high levels, driving cancer growth programs.

3

Repressors silence PC (in nucleus): High c-MYC recruits a complex of transcriptional repressors — MAX, MNT, and SIN3A — into the nucleus, where they bind the pyruvate carboxylase (PC) gene promoter and shut off PC expression.

4

Biotin's route is blocked: Without PC protein, the vitamin biotin has no enzyme to activate. The pathway from pyruvate → oxaloacetate → TCA cycle (in the mitochondria) is closed.

5

Glutamine becomes essential: With the pyruvate anaplerosis route to the mitochondria closed, the cell must use glutamine (via GLS → α-ketoglutarate) as its only way to fuel the TCA cycle. It becomes glutamine addicted.

6

Therapeutic opportunity: FBXW7-mutant cancers that are glutamine-addicted may be specifically vulnerable to glutamine-starving therapies such as CB-839 (telaglenastat), a GLS1 inhibitor in clinical trials.

Based on: Lisci M, Vericel F, Liu Y, et al. (2026). Functional nutrient-genetic profiling reveals biotin and FBXW7 are essential to bypass glutamine addiction. Molecular Cell, 86(5):901–916.e10. PMID: 41747732. doi:10.1016/j.molcel.2026.02.002 · Retrieved from PubMed, National Library of Medicine.