Pier Paolo Pandolfi
Showed that ERK directly phosphorylates and inactivates TSC2, wiring Ras/MAPK signalling into mTORC1 control, and that blocking mTORC1 in patients' tumours triggers a feedback rise in MAPK signalling
William N. Pennington Cancer Institute, Renown Health, Reno NV (since 2020) · Distinguished Honorary Professor of Cancer Genetics & Molecular Biology, University of Turin · Director of Cancer Genetics, then Cancer Research Institute, Beth Israel Deaconess Medical Center / Harvard Medical School (2007–2019) · faculty, Memorial Sloan-Kettering Cancer Center & Weill Cornell Medical College (1994–2007) · postgraduate research, Royal Postgraduate Medical School, London (Arthur Zelent lab) · MD (1989) and PhD (1995), University of Perugia
Personal website (Reno, Nevada, USA) ↗ Lab lineage1 direct trainee →
Portrait: Pier Paolo Pandolfi
Akt is the textbook route that inactivates the TSC1–TSC2 brake on mTORC1, but it isn't the only one. In 2005, Pandolfi's group showed that ERK — the kinase at the business end of the Ras/MAPK growth pathway — directly phosphorylates TSC2 at sites distinct from Akt's, and that this is enough to functionally inactivate the TSC complex on its own. That gives mTORC1 a second, independent input arm alongside PI3K/Akt and AMPK. His group extended this logic clinically in 2008, showing that inhibiting mTORC1 with rapalogs in cancer cells paradoxically activates MAPK/ERK signaling through a PI3K-dependent feedback loop — one of the key mechanistic reasons single-node mTOR inhibitors often disappoint as cancer monotherapies.
Pandolfi's research career began as an MD/PhD student in Perugia studying acute promyelocytic leukemia (APL), then continued as a postdoctoral researcher in London; his later transgenic-mouse work at Memorial Sloan-Kettering helped explain why PML-RARA-driven APL responds to retinoic acid while PLZF-RARA-driven APL does not. At Memorial Sloan-Kettering and Weill Cornell (1994–2007) his lab built one of the first Pten knockout mice, establishing PTEN as a haploinsufficient tumor suppressor. At Beth Israel Deaconess / Harvard Medical School (2007–2019) his group proposed the competing endogenous RNA (ceRNA) hypothesis — that a pseudogene's mRNA can act as a molecular 'sponge' for microRNAs and thereby regulate a protein-coding gene like PTEN.
Since 2020 Pandolfi has been based at the William N. Pennington Cancer Institute, Renown Health, in Reno, Nevada, and he is a Distinguished Honorary Professor at the University of Turin. He continues to publish on APL, PTEN/PI3K–mTOR signaling, and cancer genetics.
Milestones in the Atlas
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| Year | Evidence | Study |
|---|---|---|
| 2005 | M | Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis MA2005 Shows that ERK directly phosphorylates and inactivates TSC2, giving Ras/MAPK signaling a route into mTORC1 activation that runs independently of PI3K/Akt. |
| 2008 | M | Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer CAR2008 Shows that inhibiting mTORC1 in human cancer cells activates MAPK pathway signaling through a PI3K-dependent feedback loop. |
Co-authors in the Atlas 7
People with a profile here who share at least one study with Pier Paolo Pandolfi.
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- Arkaitz Carracedo Cancer biologist who, as first author in 2008, showed that blocking mTORC1 can switch on the MAPK pathway through a PI3K-dependent feedback loop.
- George Thomas Purified and cloned S6K1, the kinase that became the classic readout of mTORC1 activity. His lab later showed that mice lacking S6K1 resist diet-induced obesity, and that amino acids signal to mTORC1 through the lipid kinase hVps34 (GUL2008)
- Hediye Erdjument-Bromage Ran the mass-spectrometry analyses in Paul Tempst's lab at Memorial Sloan Kettering that identified the unknown proteins in the raptor, mLST8 and rictor purifications, and contributed the same approach to work on how ERK inactivates TSC2
- José Baselga Breast cancer oncologist who led the BOLERO-2 trial showing that the mTOR inhibitor everolimus added to hormone therapy lengthens progression-free survival
- Lewis C. Cantley Co-discovered PI3K, the pathway that feeds into mTOR from growth factors
- Paul Tempst Developed mass-spectrometry methods for identifying proteins from tiny samples, and led the Memorial Sloan Kettering proteomics laboratory that identified the unknown partners of mTOR in the raptor, mLST8 and rictor purifications
- Sara C. Kozma Studies the S6K/mTOR pathway and how it controls cell growth, ribosome production, diabetes and cancer, including mTOR signalling in liver cancer.
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