RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

Nichols, R. Jeremy; Haderk, Franziska; Stahlhut, Carlos; Schulze, Christopher J.; Hemmati, Golzar; Wildes, David; Tzitzilonis, Christos; Mordec, Kasia; Marquez, Abby; Romero, Jason M.; Hsieh, Tientien; Zaman, Aubhishek; Olivas, Victor; McCoach, Caroline E.; Blakely, Collin M.; Wang, Zhengping; Kiss, Gert; Koltun, Elena S.; Gill, Adrian L.; Singh, Mallika; Goldsmith, Mark A.; Smith, Jacqueline A.; Bivona, Trever G.

doi:10.1038/s41556-018-0169-1

Cited by 312 publications

(351 citation statements)

References 47 publications

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“…Thus, targeting the dominant RTK may represent an effective and tractable strategy for tumors with class III mutations. As tumors do not always harbor a single dominant RTK and may receive signals from multiple RTKs, an alternative approach to blocking upstream signaling involves the use of SHP2 inhibitors, which block a key common effector target used by multiple RTKs (69). SHP2 inhibitors have recently entered the clinic.…”

Section: Class III Braf Mutationsmentioning

confidence: 99%

Targeting Alterations in the RAF–MEK Pathway

2019

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The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer. Although RAS mutations are the most frequent MAPK alterations, less frequent alterations in downstream components of the pathway, including the RAF and MEK genes, offer promising therapeutic opportunities. In addition to BRAF V600 mutations, for which several approved therapeutic regimens exist, other alterations in the RAF and MEK genes may provide more rare, but tractable, targets. However, recent studies have illustrated the complexity of MAPK signaling and highlighted that distinct alterations in these genes may have strikingly different properties. Understanding the unique functional characteristics of specifi c RAF and MEK alterations, reviewed herein, will be critical for developing effective therapeutic approaches for these targets.Signifi cance: Alterations in the RAF and MEK genes represent promising therapeutic targets in multiple cancer types. However, given the unique and complex signaling biology of the MAPK pathway, the diverse array of RAF and MEK alterations observed in cancer can possess distinct functional characteristics. As outlined in this review, understanding the key functional properties of different RAF and MEK alterations is fundamental to selecting the optimal therapeutic approach.Research. on July 5, 2020.

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Section: Class III Braf Mutationsmentioning

confidence: 99%

Targeting Alterations in the RAF–MEK Pathway

2019

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“…SHP2 is important for the stabilization of the GRB2:SOS1/2 complexes on EGFR (42), and the mechanism of allosteric SHP2 inhibitors depends on SOS1 (43), although the contribution of SOS2 to SHP2 inhibitors was not assessed. To determine whether SOS2 deletion altered the spectrum of drug-drug synergies in EGFR-mutated cells, parallel studies were performed in EGFR-mutated cells where SOS2 was deleted (Fig.…”

Section: Assessment Of Inhibitor Landscape In Egfr-mutated Cells Linementioning

confidence: 99%

Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

Theard

Sheffels

Sealover

et al. 2020

Preprint

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Drug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR-and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.of RAS, co-targeting intermediates of the RAF/MEK/ERK and PI3K/AKT pathways enhances of osimertinib effectiveness, however, signaling through the uninhibited effector pathway may drive resistance (17)(18)(19)(20). Thus, it may be important for therapeutic combinations including osimertinib to stifle all downstream RTK/RAS signaling to be effective.Recent studies suggest that pharmacologic assessments of targeted therapeutics should be performed under 3D culture conditions rather than in 2D adherent cultures (21,22). 3D spheroids show altered growth characteristics, changes in cell surface proteins, altered metabolism, changes in activation of signaling pathways or altered responses to targeted pathway inhibitors, and are more resistant to drug-induced apoptosis compared to 2D adherent cultures signaling (23-26). These differences may be particularly relevant in EGFR-mutated NSCLC. EGFR-mutated cells show differential RTK expression and phosphorylation in 3D versus 2Dconditions (27). Further, EGFR-mutated cells respond more robustly to first-generation EGFR-TKIs in 3D cultures, and these responses more closely resemble responses seen in vivo (28).These data highlight the need for pharmacologic assessment of therapeutics designed to treat EGFR-mutated NSCLC under 3D culture conditions. The ubiquitously expressed RasGEFs (guanine nucleotide exchange factors) SOS1 and SOS2 (son of sevenless 1 and 2) are common signaling intermediates of RTK-mediated RAS activation. Although not initially considered as drug targets because of the low oncogenic potential of SOS (29), there has been renewed interest in SOS proteins as therapeutic targets for cancer treatment. We and others have shown that SOS1 and SOS2 may be important therapeutic targets in KRAS-mutated cancer cells (30-32), and a specific SOS1 inhibitor (BAY-293) has recently been identified (33). Here, we investigate SOS1 and SOS2 as potential therapeutic targets in EGFR-mutated l...

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Section: Therapeutic Clinical Trials For Individuals With Rasopathimentioning

confidence: 99%

“…These drugs have not yet been tested in children and are likely to have limited utility in individuals with RASopathies because the KRAS G12C variant is an uncommon mutation in the RASopathies. SHP2 inhibitors, which stabilize the auto‐inhibited confirmation of this phosphatase, are promising RASopathy therapeutics for all RASopathies with aberrant MAP kinase activity except for NS caused by SHP2 ( PTPN11 ) pathogenic variants (Nichols et al, ). Preclinical tool compounds that inhibit the interaction between RAS and SOS to inhibit RAS activation are currently in development and represent an exciting class of potential novel RASopathy therapeutics (Hillig et al, ).…”

Section: Introductionmentioning

confidence: 99%

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

Gross

Frone

Gripp

et al. 2020

American J of Med Genetics Pt A

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RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.

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RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

Cited by 312 publications

References 47 publications

Targeting Alterations in the RAF–MEK Pathway

Targeting Alterations in the RAF–MEK Pathway

Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

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