PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer

Amante, Romain J.; Jehanno, Charly; Silva, Duvini De; Coissieux, Marie–May; Ackerknecht, Markus; Romanet, Vincent; Sethi, Atul; Hamelin, Baptiste; Preca, Bogdan‐Tiberius; Piscuoglio, Salvatore; Ng, Charlotte K.Y.; Mohseni, Morvarid; Richina, Veronica

doi:10.1007/s10911-023-09539-9

Cited by 3 publications

(5 citation statements)

References 47 publications

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“…Overall, SDUY038 , as a novel SHP2 allosteric inhibitor, exhibited broad antitumor activity against a range of cancer cell lines by downregulating pERK levels and disrupting the MAPK signaling pathway. It is also noteworthy that pAKT was barely detectable with the treatment of 10 μM SDUY038 , which surpasses the effect of 20 μM SHP099 in the MDA-MB-468 cell line, underscoring the potential of the PI3K/AKT signaling pathway in modulating the antiproliferative activity of SDUY038 .…”

Section: Resultsmentioning

confidence: 95%

“…SHP2 acts as an upstream regulator of cell survival and involves in various crucial signaling cascades, including the RAS/ERK/MAPK and PI3K/AKT signaling pathways. , To investigate the effect of SDUY038 on the phosphorylation level of ERK, Western blotting analysis was performed on a panel of cell lines, including MDA-MB-468, 4T1, SW480, HCT116, RT4 and KYSE520, following the drug treatment (Figure S4). As anticipated, SDUY038 led to a dose-dependent decrease in pERK levels after 24-h treatment, particularly evident in MDA-MB-468 and 4T1 cell lines, which is consistent with its antiproliferative activity.…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold

Zhu,

Zhao,

Yang

et al. 2024

J. Med. Chem.

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SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (K D = 0.29 μM), enzymatic activity (IC50 = 1.2 μM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7–24 μM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t 1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold

Zhu,

Zhao,

Yang

et al. 2024

J. Med. Chem.

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“…Consistently, it has also been observed that the coinhibition of SHP2 and PI3K can correct MPD by disrupting p85/SHP2/GAB2 interaction. Moreover, it has been demonstrated that SHP2 also plays a critical role in the development of resistance to PI3K inhibitors, as shown in the preclinical models of metastatic breast cancer where the combination of PI3K and SHP2 inhibition not only results in synergistic tumor growth inhibition but also inhibits metastasis formation ( 44 ). The role of the PI3K/SHP2 axis in the regulation of metastatic progression has also been demonstrated by overexpression experiments in ovarian tumor models ( 45 ).…”

Section: Other Pathways Regulated By Shp2mentioning

confidence: 99%

SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment

Sodir,

Pathria,

Adamkewicz

et al. 2023

Cancer Discovery

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The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. Significance: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.

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“…Targeting SHP2 via a selective inhibitor such as SHP099 (35) effectively inhibits the MAPK pathway and counteracts therapeutic resistance when combined with a MEK inhibitor in mutant KRAS-driven cancers (14)(15)(16). While MAPK inhibition via SHP099 in combination with PI3K inhibitors has shown efficacy in other types of cancer (36,37), it remains to be investigated in PDAC. The drug Omipalisib is a potent inhibitor of PI3K complex components p110α/β/δ/γ and downstream factors mTORC1/2, ultimately suppressing activation of AKT (38).…”

Section: Introductionmentioning

confidence: 99%

“…Combined MEK inhibition and PI3K pathway inhibition (via AKT or mTOR) have shown effectiveness in PDAC as well as other cancers (18,26,(39)(40)(41)(42)(43)(44). While MAPK inhibition via SHP099 in combination with PI3K inhibitors has shown efficacy in a few cancers (36,37), it remains to be investigated in PDAC. Omipalisib has been investigated clinically as a single therapeutic agent in solid tumors, but its efficacy was modest, suggesting that further investigation into an optimal combination treatment strategy is needed (45).…”

Section: Introductionmentioning

confidence: 99%

Combined PI3K and MAPK inhibition synergizes to suppress PDAC

Bye,

Jack,

Pierce

et al. 2023

Preprint

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Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS as well as its target MAPK pathway effectors have shown limited success due to the difficulty to pharmacologically target KRAS, inherent drug resistance in PDAC cells, and acquired resistance through activation of alternative mitogenic pathways such JAK-STAT and PI3K-AKT. While KRAS canonically drives the MAPK signaling pathway via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Our therapeutic study targeted the PI3K-AKT pathway with the drug Omipalisib (p110alpha/beta/delta/gamma and mTORC1/2 inhibitor) in combination with MAPK pathway targeting drug Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099), which is an inhibitor of the KRAS effector SHP2. Western blot analysis demonstrated that application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT) and in some instances increased pAKT levels. Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MEK and PI3K-AKT, to more effectively suppress pancreatic cancer. In vitro studies demonstrated that both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were generally more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. Additionally, we found that while combination Omipalisib/SHP099 treatment reduced implanted tumor growth in vivo, the Omipalisib/Trametinib treatment was significantly more effective. Therefore, we additionally tested the Omipalisib/Trametinib combination therapeutic in the highly aggressive PKT (Ptf1acre, LSL-KrasG12D, TGFbR2fl/fl) spontaneous mouse model of PDAC. We subsequently found that PKT mice treated with the Omipalisib/Trametinib combination therapeutic survived significantly longer than mice treated with either drug alone, and more than doubled the mean survival time of vehicle control mice. Altogether, our data support the importance of a dual treatment strategy targeting both MAPK and PI3K-AKT pathways.

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PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer

Cited by 3 publications

References 47 publications

Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold

Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold

SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment

Combined PI3K and MAPK inhibition synergizes to suppress PDAC

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