Sonia Lain Group
Our research involves discovery and elucidation of the mechanisms of action of tumour selective compounds.
Discovery and elucidation of the mechanisms of action of tumour selective compounds
Activating p53 has long been considered as an attractive strategy to treat cancer. Since 2004, the most specific approach to activate wildtype p53 without damaging DNA is to use inhibitors of mdm2 with peptides or small molecules such as nutlin3 (Vassilev et al., Science, 2004). However, and in spite of the enormous efforts of academia and industry, mdm2 inhibitors have yet to deliver in the clinic. This slow progress may be due to lack of selectivity for cancer cells or because many cancer cell types tend to undergo a reversible cell cycle arrest. An additional concern is that mdm2 inhibitors such as nutlin3 can lead a significant proportion of cells to accumulate in G2. This effect, which also occurs in cultures of normal cells such as primary fibroblasts could have undesired consequences. Indeed, as demonstrated by others, when the mdm2 inhibitor is removed G2 cells can enter S phase leading to the appearance of 8N cells and increasing the risk of genome instability.
Although less selective for the p53 pathway than mdm2 inhibitors, numerous other small molecules activating wild type p53 have been described. Of these, a large number happen to be inhibitors of the enzyme dihydroorotate dehydrogenase DHODH, a mitochondrial enzyme coupled to the electron transport chain that is involved in the de novo synthesis of uridine 5’-monophosphate (UMP) and therefore, of all pyrimidine ribonucleotides. As such, DHODH inhibitors are used in the clinic for the control of autoimmune diseases and are in clinical trial as antivirals. With regards to cancer, it is well established that inhibition of UMP synthesis can lead to the accumulation of cancer cells in S phase, a very vulnerable stage of the cell cycle and where p53 activation may cause cell death more easily. In addition, DHODH inhibitors can promote differentiation of leukemic cells, which is why several DHODH inhibitors have entered clinical trials for acute myeloid leukemia.
Aside from blood cancer cells, several cell lines from solid cancers respond to DHODH inhibitors in culture. However, the results in vivo are less impressive. One possible reason for this is that the levels of uridine in plasma can supplement UMP production and therefore rescue cells from DHODH inhibition.
After identifying a number of inhibitors of DHODH, our current work focuses on identifying solid cancers that are hypersensitive to DHODH inhibition and developing strategies to enhance the cancer cell killing effect of DHODH inhibitors whilst sparing normal cells and reducing the impact of DHODH inhibition on the immune system.
DHODH inhibition modulates glucose metabolism and circulating GDF15, and improves metabolic balance.
Zhang J, Terán G, Popa M, Madapura H, Ladds MJGW, Lianoudaki D, Grünler J, Arsenian-Henriksson M, McCormack E, Rottenberg ME, Catrina SB, Laín S, Darekar S.
iScience. 2021 May 1;24(5):102494.
Modulating pyrimidine ribonucleotide levels for the treatment of cancer.
Mollick T, Laín S
Cancer Metab 2020 ;8():12
Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability.
Popova G, Ladds MJGW, Johansson L, Saleh A, Larsson J, Sandberg L, Sahlberg SH, Qian W, Gullberg H, Garg N, Gustavsson AL, Haraldsson M, Lane D, Yngve U, Lain S
J Med Chem 2020 04;63(8):3915-3934
Functional characterization of novel germline TP53 variants in Swedish families.
Kharaziha P, Ceder S, Axell O, Krall M, Fotouhi O, Böhm S, Lain S, Borg Å, Larsson C, Wiman KG, Tham E, Bajalica-Lagercrantz S
Clin Genet 2019 09;96(3):216-225
Small molecule activators of the p53 response.
Ladds MJGW, Laín S
J Mol Cell Biol 2019 03;11(3):245-254
Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive.
Keszei M, Record J, Kritikou JS, Wurzer H, Geyer C, Thiemann M, Drescher P, Brauner H, Köcher L, James J, He M, Baptista MA, Dahlberg CI, Biswas A, Lain S, Lane DP, Song W, Pütsep K, Vandenberghe P, Snapper SB, Westerberg LS
J Clin Invest 2018 08;128(9):4115-4131
Mass Spectrometry Reveals the Direct Action of a Chemical Chaperone.
Gault J, Lianoudaki D, Kaldmäe M, Kronqvist N, Rising A, Johansson J, Lohkamp B, Laín S, Allison TM, Lane DP, Marklund EG, Landreh M
J Phys Chem Lett 2018 Jul;9(14):4082-4086
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
Ladds MJGW, van Leeuwen IMM, Drummond CJ, Chu S, Healy AR, Popova G, Pastor Fernández A, Mollick T, Darekar S, Sedimbi SK, Nekulova M, Sachweh MCC, Campbell J, Higgins M, Tuck C, Popa M, Safont MM, Gelebart P, Fandalyuk Z, Thompson AM, Svensson R, Gustavsson AL, Johansson L, Färnegårdh K, Yngve U, Saleh A, Haraldsson M, D'Hollander ACA, Franco M, Zhao Y, Håkansson M, Walse B, Larsson K, Peat EM, Pelechano V, Lunec J, Vojtesek B, Carmena M, Earnshaw WC, McCarthy AR, Westwood NJ, Arsenian-Henriksson M, Lane DP, Bhatia R, McCormack E, Laín S
Nat Commun 2018 03;9(1):1107
Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib.
Ladds MJGW, Pastor-Fernández A, Popova G, van Leeuwen IMM, Eng KE, Drummond CJ, Johansson L, Svensson R, Westwood NJ, McCarthy AR, Tholander F, Popa M, Lane DP, McCormack E, McInerney GM, Bhatia R, Laín S
PLoS One 2018 ;13(4):e0195956
Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase.
Costeira-Paulo J, Gault J, Popova G, Ladds MJGW, van Leeuwen IMM, Sarr M, Olsson A, Lane DP, Laín S, Marklund EG, Landreh M
Cell Chem Biol 2018 03;25(3):309-317.e4
cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response.
Madapura HS, Salamon D, Wiman KG, Lain S, Klein E, Nagy N
Cell Cycle 2016 05;15(9):1267-75
Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells.
Sachweh MC, Stafford WC, Drummond CJ, McCarthy AR, Higgins M, Campbell J, Brodin B, Arnér ES, Laín S
Oncotarget 2015 Jun;6(18):16488-506
Acetylation site specificities of lysine deacetylase inhibitors in human cells.
Schölz C, Weinert BT, Wagner SA, Beli P, Miyake Y, Qi J, Jensen LJ, Streicher W, McCarthy AR, Westwood NJ, Lain S, Cox J, Matthias P, Mann M, Bradner JE, Choudhary C
Nat Biotechnol 2015 Apr;33(4):415-23
SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth.
Ma L, Maruwge W, Strambi A, D'Arcy P, Pellegrini P, Kis L, de Milito A, Lain S, Brodin B
Cell Death Dis 2014 Oct;5():e1483
SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells.
Li L, Osdal T, Ho Y, Chun S, McDonald T, Agarwal P, Lin A, Chu S, Qi J, Li L, Hsieh YT, Dos Santos C, Yuan H, Ha TQ, Popa M, Hovland R, Bruserud Ø, Gjertsen BT, Kuo YH, Chen W, Lain S, McCormack E, Bhatia R
Cell Stem Cell 2014 Oct;15(4):431-446
Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6.
MacCallum SF, Groves MJ, James J, Murray K, Appleyard V, Prescott AR, Drbal AA, Nicolaou A, Cunningham J, Haydock S, Ganley IG, Westwood NJ, Coates PJ, Lain S, Tauro S
Sci Rep 2013 ;3():1275
Incompatible effects of p53 and HDAC inhibition on p21 expression and cell cycle progression.
Sachweh MC, Drummond CJ, Higgins M, Campbell J, Laín S
Cell Death Dis 2013 Mar;4():e533
Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2.
van Leeuwen IM, Higgins M, Campbell J, McCarthy AR, Sachweh MC, Navarro AM, Laín S
Mol Cancer Ther 2013 Apr;12(4):471-80
Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner.
McCarthy AR, Sachweh MC, Higgins M, Campbell J, Drummond CJ, van Leeuwen IM, Pirrie L, Ladds MJ, Westwood NJ, Laín S
Mol Cancer Ther 2013 Apr;12(4):352-60
p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP.
Madapura HS, Salamon D, Wiman KG, Lain S, Klein G, Klein E, Nagy N
Cell Cycle 2012 Dec;11(24):4563-9
An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells.
van Leeuwen IM, Rao B, Sachweh MC, Laín S
Cell Cycle 2012 May;11(9):1851-61
Synthesis and biological characterisation of sirtuin inhibitors based on the tenovins.
McCarthy AR, Pirrie L, Hollick JJ, Ronseaux S, Campbell J, Higgins M, Staples OD, Tran F, Slawin AM, Lain S, Westwood NJ
Bioorg Med Chem 2012 Mar;20(5):1779-93
Pharmacological manipulation of the cell cycle and metabolism to protect normal tissues against conventional anticancer drugs.
van Leeuwen IM, Laín S
Oncotarget 2011 Apr;2(4):274-6
Mechanism-specific signatures for small-molecule p53 activators.
van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, Westwood NJ, Laín S
Cell Cycle 2011 May;10(10):1590-8
Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy.
Rao B, van Leeuwen IM, Higgins M, Campbel J, Thompson AM, Lane DP, Lain S
Oncotarget 2010 Nov;1(7):639-50
Dynamic energy budget approaches for modelling organismal ageing.
van Leeuwen IM, Vera J, Wolkenhauer O
Philos Trans R Soc Lond B Biol Sci 2010 Nov;365(1557):3443-54
p53-based cancer therapy.
Lane DP, Cheok CF, Lain S
Cold Spring Harb Perspect Biol 2010 Sep;2(9):a001222
Drug discovery in the p53 field.
Semin Cancer Biol 2010 Feb;20(1):1-2