CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors

Wang, Jiawan; Calizo, Ana; Zhang, Lindy; Pino, James C.; Lyu, Yang; Pollard, Kai; Zhang, Xiaochun; Larsson, Alex T.; Conniff, Eric; Llosa, Nicolas J.; Wood, David K.; Largaespada, David A.; Moody, Susan E.; Gosline, Sara J.; Hirbe, Angela C.; Pratilas, Christine A.

doi:10.1126/sciadv.adg8876

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors

Journal Article · Fri Nov 24 00:00:00 EST 2023 · Science Advances

DOI:https://doi.org/10.1126/sciadv.adg8876· OSTI ID:2221919

^[1]; ^[1]; ^[1]; ^[2]; ^[3]; Pollard, Kai ^[1]; Zhang, Xiaochun ^[3]; ^[4]; Conniff, Eric ^[4]; ^[1]; ^[4]; ^[4]; ^[5]; ^[2]; ^[3]; ^[1]

Johns Hopkins University, Baltimore, MD (United States). School of Medicine
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Washington University, St. Louis, MO (United States)
University of Minnesota, Minneapolis, MN (United States)
Novartis Institutes for Biomedical Research, Cambridge, MA (United States)

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: Children’s Cancer Foundation; Hyundai Hope on Wheels; NF Research Initiative; Neurofibromatosis Therapeutic Acceleration Program; Novartis Institute for Biomedical Research; SKCCC Cancer Center Core National Institutes of Health; USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2221919

Report Number(s):: PNNL-SA--181806

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 47 Vol. 9; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

References (68)

Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases Ducatman, Barbara S.; Scheithauer, Bernd W.; Piepgras, David G. Cancer, Vol. 57, Issue 10 https://doi.org/10.1002/1097-0142(19860515)57:10<2006::AID-CNCR2820571022>3.0.CO;2-6	journal	May 1986
Gene Set Knowledge Discovery with Enrichr Xie, Zhuorui; Bailey, Allison; Kuleshov, Maxim V. Current Protocols, Vol. 1, Issue 3 https://doi.org/10.1002/cpz1.90	journal	March 2021
The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. Kitagawa, M.; Higashi, H.; Jung, H. K. The EMBO Journal, Vol. 15, Issue 24 https://doi.org/10.1002/j.1460-2075.1996.tb01097.x	journal	December 1996
Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of neurofibromatosis type 1 Jousma, Edwin; Rizvi, Tilat A.; Wu, Jianqiang Pediatric Blood & Cancer, Vol. 62, Issue 10 https://doi.org/10.1002/pbc.25546	journal	April 2015
The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21 Martin, George A.; Viskoohil, David; Bollag, Gideon Cell, Vol. 63, Issue 4 https://doi.org/10.1016/0092-8674(90)90150-D	journal	November 1990
The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early xenopus development Tang, Terry L.; Freeman, Robert M.; O'Reilly, Alana M. Cell, Vol. 80, Issue 3 https://doi.org/10.1016/0092-8674(95)90498-0	journal	February 1995
Intermittent dosing of RMC-4630, a potent, selective inhibitor of SHP2, combined with the MEK inhibitor cobimetinib, in a phase 1b/2 clinical trial for advanced solid tumors with activating mutations of RAS signaling Bendell, J.; Ulahannan, S.; Koczywas, M. European Journal of Cancer, Vol. 138 https://doi.org/10.1016/S0959-8049(20)31089-3	journal	October 2020
Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2 Gavrieli, Maya; Watanabe, Norihiko; Loftin, Susan K. Biochemical and Biophysical Research Communications, Vol. 312, Issue 4 https://doi.org/10.1016/j.bbrc.2003.11.070	journal	December 2003
Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition Álvarez-Fernández, Mónica; Malumbres, Marcos Cancer Cell, Vol. 37, Issue 4 https://doi.org/10.1016/j.ccell.2020.03.010	journal	April 2020
PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs Prahallad, Anirudh; Heynen, Guus J. J. E.; Germano, Giovanni Cell Reports, Vol. 12, Issue 12 https://doi.org/10.1016/j.celrep.2015.08.037	journal	September 2015
High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition Cai, Jinyang; Jacob, Sheeba; Kurupi, Richard Cell Reports, Vol. 40, Issue 4 https://doi.org/10.1016/j.celrep.2022.111095	journal	July 2022
TORC1 Is Essential for NF1-Associated Malignancies Johannessen, Cory M.; Johnson, Bryan W.; Williams, Sybil M. Genther Current Biology, Vol. 18, Issue 1 https://doi.org/10.1016/j.cub.2007.11.066	journal	January 2008
The promise of signal transduction in genetically driven sarcomas of the nerve Kim, AeRang; Pratilas, Christine A. Experimental Neurology, Vol. 299 https://doi.org/10.1016/j.expneurol.2017.08.014	journal	January 2018
Processes in DNA damage response from a whole-cell multi-omics perspective Pino, James C.; Lubbock, Alexander L. R.; Harris, Leonard A. iScience, Vol. 25, Issue 11 https://doi.org/10.1016/j.isci.2022.105341	journal	November 2022
Deciphering the retinoblastoma protein phosphorylation code Rubin, Seth M. Trends in Biochemical Sciences, Vol. 38, Issue 1 https://doi.org/10.1016/j.tibs.2012.10.007	journal	January 2013
Discovery of a Novel Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) and Cyclin-Dependent Kinase 4 (CDK4) Dual Inhibitor for the Treatment of Triple-Negative Breast Cancer Chen, Xiaoyu; Shu, Chengxia; Li, Wenqiang Journal of Medicinal Chemistry, Vol. 65, Issue 9 https://doi.org/10.1021/acs.jmedchem.2c00063	journal	April 2022
BRAF mutation predicts sensitivity to MEK inhibition Solit, David B.; Garraway, Levi A.; Pratilas, Christine A. Nature, Vol. 439, Issue 7074 https://doi.org/10.1038/nature04304	journal	November 2005
PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies De Raedt, Thomas; Beert, Eline; Pasmant, Eric Nature, Vol. 514, Issue 7521 https://doi.org/10.1038/nature13561	journal	August 2014
Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases Chen, Ying-Nan P.; LaMarche, Matthew J.; Chan, Ho Man Nature, Vol. 535, Issue 7610 https://doi.org/10.1038/nature18621	journal	June 2016
Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis Bunda, Severa; Burrell, Kelly; Heir, Pardeep Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms9859	journal	November 2015
PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors Lee, William; Teckie, Sewit; Wiesner, Thomas Nature Genetics, Vol. 46, Issue 11 https://doi.org/10.1038/ng.3095	journal	September 2014
Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors Zhang, Ming; Wang, Yuxuan; Jones, Sian Nature Genetics, Vol. 46, Issue 11 https://doi.org/10.1038/ng.3116	journal	October 2014
Salmon provides fast and bias-aware quantification of transcript expression Patro, Rob; Duggal, Geet; Love, Michael I. Nature Methods, Vol. 14, Issue 4 https://doi.org/10.1038/nmeth.4197	journal	March 2017
Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAF Xing, F.; Persaud, Y.; Pratilas, C. A. Oncogene, Vol. 31, Issue 4 https://doi.org/10.1038/onc.2011.250	journal	July 2011
Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2 Pack, Lindsey R.; Daigh, Leighton H.; Chung, Mingyu Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-23612-z	journal	June 2021
Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy Gharbi, Severine Isabelle; Pelletier, Laura A.; Espada, Alfonso npj Breast Cancer, Vol. 8, Issue 1 https://doi.org/10.1038/s41523-022-00494-y	journal	November 2022
RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers Nichols, Robert J.; Haderk, Franziska; Stahlhut, Carlos Nature Cell Biology, Vol. 20, Issue 9 https://doi.org/10.1038/s41556-018-0169-1	journal	August 2018
Strelka2: fast and accurate calling of germline and somatic variants Kim, Sangtae; Scheffler, Konrad; Halpern, Aaron L. Nature Methods, Vol. 15, Issue 8 https://doi.org/10.1038/s41592-018-0051-x	journal	July 2018
Cellpose: a generalist algorithm for cellular segmentation Stringer, Carsen; Wang, Tim; Michaelos, Michalis Nature Methods, Vol. 18, Issue 1 https://doi.org/10.1038/s41592-020-01018-x	journal	December 2020
A clinically and genomically annotated nerve sheath tumor biospecimen repository Pollard, Kai; Banerjee, Jineta; Doan, Xengie Scientific Data, Vol. 7, Issue 1 https://doi.org/10.1038/s41597-020-0508-5	journal	June 2020
The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation Brohl, Andrew S.; Kahen, Elliot; Yoder, Sean J. Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-15183-1	journal	November 2017
RB and cell cycle progression Giacinti, C.; Giordano, A. Oncogene, Vol. 25, Issue 38 https://doi.org/10.1038/sj.onc.1209615	journal	August 2006
A high-throughput microtissue platform to probe endothelial function in vitro Crampton, Alexandra L.; Cummins, Katherine A.; Wood, David K. Integrative Biology, Vol. 10, Issue 9 https://doi.org/10.1039/C8IB00111A	journal	January 2018
Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas Dombi, Eva; Baldwin, Andrea; Marcus, Leigh J. New England Journal of Medicine, Vol. 375, Issue 26 https://doi.org/10.1056/NEJMoa1605943	journal	December 2016
Selumetinib in Children with Inoperable Plexiform Neurofibromas Gross, Andrea M.; Wolters, Pamela L.; Dombi, Eva New England Journal of Medicine, Vol. 382, Issue 15 https://doi.org/10.1056/NEJMoa1912735	journal	April 2020
The NF1 tumor suppressor critically regulates TSC2 and mTOR Johannessen, Cory M.; Reczek, Elizabeth E.; James, Marianne F. Proceedings of the National Academy of Sciences, Vol. 102, Issue 24 https://doi.org/10.1073/pnas.0503224102	journal	June 2005
V600EBRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway Pratilas, C. A.; Taylor, B. S.; Ye, Q. Proceedings of the National Academy of Sciences, Vol. 106, Issue 11 https://doi.org/10.1073/pnas.0900780106	journal	February 2009
Deletion of the p27 ^Kip1 gene restores normal development in cyclin D1-deficient mice Geng, Yan; Yu, Qunyan; Sicinska, Ewa Proceedings of the National Academy of Sciences, Vol. 98, Issue 1 https://doi.org/10.1073/pnas.98.1.194	journal	December 2000
Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2 Yokosuka, Tadashi; Takamatsu, Masako; Kobayashi-Imanishi, Wakana The Journal of Experimental Medicine, Vol. 209, Issue 6 https://doi.org/10.1084/jem.20112741	journal	May 2012
A High-Throughput Workflow to Study Remodeling of Extracellular Matrix-Based Microtissues Crampton, Alexandra L.; Cummins, Katherine A.; Wood, David K. Tissue Engineering Part C: Methods, Vol. 25, Issue 1 https://doi.org/10.1089/ten.tec.2018.0290	journal	January 2019
Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads Ye, K.; Schulz, M. H.; Long, Q. Bioinformatics, Vol. 25, Issue 21 https://doi.org/10.1093/bioinformatics/btp394	journal	June 2009
Trimmomatic: a flexible trimmer for Illumina sequence data Bolger, Anthony M.; Lohse, Marc; Usadel, Bjoern Bioinformatics, Vol. 30, Issue 15 https://doi.org/10.1093/bioinformatics/btu170	journal	April 2014
SynergyFinder 3.0: an interactive analysis and consensus interpretation of multi-drug synergies across multiple samples Ianevski, Aleksandr; Giri, Anil K.; Aittokallio, Tero Nucleic Acids Research, Vol. 50, Issue W1 https://doi.org/10.1093/nar/gkac382	journal	May 2022
Calling Somatic SNVs and Indels with Mutect2 Benjamin, David; Sato, Takuto; Cibulskis, Kristian https://doi.org/10.1101/861054	preprint	December 2019
VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing Koboldt, D. C.; Zhang, Q.; Larson, D. E. Genome Research, Vol. 22, Issue 3 https://doi.org/10.1101/gr.129684.111	journal	February 2012
Human Papillomavirus Carcinogenesis: an Identity Crisis in the Retinoblastoma Tumor Suppressor Pathway Munger, Karl; Jones, D. Leanne Journal of Virology, Vol. 89, Issue 9 https://doi.org/10.1128/JVI.03486-14	journal	May 2015
Abrogation of growth arrest signals by human papillomavirus type 16 E7 is mediated by sequences required for transformation Demers, G. W.; Espling, E.; Harry, J. B. Journal of Virology, Vol. 70, Issue 10 https://doi.org/10.1128/jvi.70.10.6862-6869.1996	journal	October 1996
Malignant peripheral nerve sheath tumours in neurofibromatosis 1 Evans, D. G. R. Journal of Medical Genetics, Vol. 39, Issue 5 https://doi.org/10.1136/jmg.39.5.311	journal	May 2002
Activating Mutations of the Noonan Syndrome-Associated *SHP2/PTPN11* Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia Bentires-Alj, Mohamed; Paez, J. Guillermo; David, Frank S. Cancer Research, Vol. 64, Issue 24 https://doi.org/10.1158/0008-5472.CAN-04-1923	journal	December 2004
RABL6A Promotes G1–S Phase Progression and Pancreatic Neuroendocrine Tumor Cell Proliferation in an Rb1-Dependent Manner Hagen, Jussara; Muniz, Viviane P.; Falls, Kelly C. Cancer Research, Vol. 74, Issue 22 https://doi.org/10.1158/0008-5472.CAN-13-3742	journal	November 2014
Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors Wang, Jiawan; Pollard, Kai; Allen, Amy N. Cancer Research, Vol. 80, Issue 23 https://doi.org/10.1158/0008-5472.CAN-20-1365	journal	December 2020
Activation of Receptor Tyrosine Kinases Mediates Acquired Resistance to MEK Inhibition in Malignant Peripheral Nerve Sheath Tumors Wang, Jiawan; Pollard, Kai; Calizo, Ana Cancer Research, Vol. 81, Issue 3 https://doi.org/10.1158/0008-5472.CAN-20-1992	journal	February 2021
RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors Kohlmeyer, Jordan L.; Kaemmer, Courtney A.; Pulliam, Casey Clinical Cancer Research, Vol. 26, Issue 12 https://doi.org/10.1158/1078-0432.CCR-19-2706	journal	June 2020
Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling Liu, Chen; Lu, Hengyu; Wang, Hongyun Clinical Cancer Research, Vol. 27, Issue 1 https://doi.org/10.1158/1078-0432.CCR-20-2718	journal	October 2020
NF1 Deletion Generates Multiple Subtypes of Soft-Tissue Sarcoma That Respond to MEK Inhibition Dodd, Rebecca D.; Mito, Jeffrey K.; Eward, William C. Molecular Cancer Therapeutics, Vol. 12, Issue 9 https://doi.org/10.1158/1535-7163.MCT-13-0189	journal	September 2013
Abstract 1322: Maximizing the therapeutic potential of SHP2 inhibition with rational combination strategies in tumors driven by aberrant RAS-MAPK signaling Lee, Grace J.; Stahlhut, Carlos; Evans, James Cancer Research, Vol. 79, Issue 13_Supplement https://doi.org/10.1158/1538-7445.AM2019-1322	journal	July 2019
Abstract 2837: Dual inhibition of SHP2 and CDK4/6 leads to immunological memory and immune-mediated anti-tumor activity in a mouse syngeneic model of breast cancer Shifrin, Nataliya Tovbis; Lee, Grace J.; Omaque, Neil Cancer Research, Vol. 80, Issue 16_Supplement https://doi.org/10.1158/1538-7445.AM2020-2837	journal	August 2020
SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Fedele, Carmine; Ran, Hao; Diskin, Brian Cancer Discovery, Vol. 8, Issue 10 https://doi.org/10.1158/2159-8290.CD-18-0444	journal	July 2018
MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors Jessen, Walter J.; Miller, Shyra J.; Jousma, Edwin Journal of Clinical Investigation, Vol. 123, Issue 1 https://doi.org/10.1172/JCI60578	journal	December 2012
Chromosome 8 gain is associated with high-grade transformation in MPNST Dehner, Carina; Moon, Chang In; Zhang, Xiyuan JCI Insight, Vol. 6, Issue 6 https://doi.org/10.1172/jci.insight.146351	journal	March 2021
Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients Shurell, Elizabeth; Tran, Linh M.; Nakashima, Jonathan BMC Cancer, Vol. 14, Issue 1 https://doi.org/10.1186/1471-2407-14-827	journal	November 2014
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Love, Michael I.; Huber, Wolfgang; Anders, Simon Genome Biology, Vol. 15, Issue 12 https://doi.org/10.1186/s13059-014-0550-8	journal	December 2014
The Ensembl Variant Effect Predictor McLaren, William; Gil, Laurent; Hunt, Sarah E. Genome Biology, Vol. 17, Issue 1 https://doi.org/10.1186/s13059-016-0974-4	journal	June 2016
Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)–associated plexiform neurofibroma: A phase I/IIa study. McCowage, Geoffrey Brian; Mueller, Sabine; Pratilas, Christine A. Journal of Clinical Oncology, Vol. 36, Issue 15_suppl https://doi.org/10.1200/JCO.2018.36.15_suppl.10504	journal	May 2018
Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors. Brana, Irene; Shapiro, Geoffrey; Johnson, Melissa Lynne Journal of Clinical Oncology, Vol. 39, Issue 15_suppl https://doi.org/10.1200/JCO.2021.39.15_suppl.3005	journal	May 2021
Protein tyrosine phosphatases in the JAK/STAT pathway Xu, Dan Frontiers in Bioscience, Vol. Volume, Issue 13 https://doi.org/10.2741/3051	journal	January 2008
The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes Paternot, Sabine; Colleoni, Bianca; Bisteau, Xavier Cell Cycle, Vol. 13, Issue 18 https://doi.org/10.4161/15384101.2014.946841	journal	September 2014
Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy Gharbi, Severine Isabelle; Pelletier, Laura A.; Espada, Alfonso figshare https://doi.org/10.6084/m9.figshare.17748092	dataset	January 2022

Similar Records

Alterations at chromosome 17 loci in peripheral nerve sheath tumors

Journal Article · Sat Dec 31 23:00:00 EST 1994 · Journal of Neuropathology and Experimental Neurology · OSTI ID:447014

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

Journal Article · Sun May 28 20:00:00 EDT 2023 · Neuro-Oncology · OSTI ID:2305670

Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy

Journal Article · Mon Nov 28 19:00:00 EST 2022 · npj Breast Cancer · OSTI ID:2423333

Related Subjects

60 APPLIED LIFE SCIENCES
MPNST
NF1
cancer

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors

Citation Formats

References (68)

Similar Records

Related Subjects