MiaPaCa-2 xenografts SHP2i + ERKi
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE213697 | GEO | 2022/11/15
REPOSITORIES: GEO
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Project description:KRAS mutant pancreatic tumors have poor prognosis and few therapeutic options. Here, Frank et al. show that the combination of RMC4550 (SHP2 inhibitor) and LY3214996 (ERK inhibitor) effectively impairs tumor growth and induces tumor regression in multiplein vivo models of PDAC .
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Project description:MiaPaCa-2 xenografts SHP2i + ERKi
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Project description:KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime goal. Recently, inhibitors (G12C-Is) that bind KRAS-G12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRAS-G12C activation and inhibitor engagement, we found that SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRAS-G12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. The combination of SHP2-I and G12C-I evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using an inhibitor-resistant SHP2 mutant showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but SHP2-Is also had direct effects on angiogenesis. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies. G12C-Is show significant, but limited, efficacy as single agents, in part because of “adaptive resistance”. We find that combining G12C-Is with SHP2-Is abrogates adaptive resistance and results in favorable changes in the immune microenvironment that potentiate PD-1 blockade in KRAS-mutant malignancies. SHP2-Is also can have direct, context-dependent, effects on tumor vasculature.
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Project description:HCC tumors have poor prognosis and few therapeutic options. Here, Mulero-Sánchez et al. show that the combination of SHP2 inhibitors and mTOR inhibitor) effectively impairs tumor growth in vitro and in vivo.
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Project description:SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion and promoted B and T lymphocyte infiltration in Kras- and Egfr- mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with limited effective treatment options. PDAC tumors frequently harbor the constitutively activated form of KRAS which drives proliferative signaling, but directly targeting KRAS has so far been unsuccessful. To overcome this limitation, combinatorial treatment strategies have been developed to inhibit upstream activators and downstream effectors of KRAS signaling. One such combination using trametinib, a MEK1/2 inhibitor, and lapatinib, an EGFR/HER2 inhibitor, substantially reduced tumor growth in a patient-derived xenograft (PDX) model of PDAC. Although trametinib and lapatinib are both known to inhibit the canonical MAPK signaling cascade, the effects of this combination on other important pathways in pancreatic cancer remains unclear. To investigate this, we analyze global gene expression profiles from PDX models of PDAC treated with trametinib, lapatinib, or their combination. Our results show that trametinib induces similar yet less significant expression changes compared to combination while lapatinib has little to no effect as a monotherapy in the acute treatment setting. In the chronic treatment setting, we show that tumors exposured to prolonged treatment with trametinib plus lapatinib eventually leads to adapative resistance. Expression analyses of resistant tumors revealed concominant gene expression changes in upstream receptor tyrosine kinases (RTKs).
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Project description:The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTKs), as it is required for full RAS-ERK activation to promote cell proliferation and survival programs. SHP2 allosteric inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and they are currently being tested in clinical trials for tumors with over-activation of the RAS/ERK pathway, alone and in various drug combinations. Using in vitro models, we established acquired resistant cell lines to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. We performed both label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics to reveal that AML cells can restore phosphorylated ERK (pERK) in presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induces the tyrosine phosphorylation and feedback-activation of the FLT3 receptor, which in turn phosphorylates SHP2 on Tyrosine 62. This phosphorylation stabilizes SHP2 in its open conformation, preventing SHP099 binding, thus resulting in resistance. Combinatorial inhibition of SHP2 and MEK or SHP2 and FLT3 prevents pERK rebound and resistant cell growth. We observed the same mechanism in a FLT3-mutated B-ALL cell line and in the inv(16)/KITD816Y AML mouse model. Finally, we show that allosteric SHP2 inhibition does not impair the clonogenic ability of normal bone marrow progenitors, supporting its future use for clinical applications.
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Project description:The overall 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is only 13% and there is an unmet need for better therapies. For the minority (5-10%) of patients with homologous recombination repair (HRR) deficient PDAC tumors (BRCA1/2, PALB2 mutations), poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) and platinum-based therapies offer the best-personalized treatment approach. However, the efficacy of these treatments is often limited due to inherent (HRR proficient tumors) or acquired drug resistance. We have previously shown that expression of BARD1 or BRCA1- Associated- Ring- Domain- 1, a DNA repair protein and an obligate binding partner of BRCA1, is post-transcriptionally upregulated by the pro-survival RNA binding protein HuR (ELAVL-1), in PDAC. Here, we evaluated BARD1’s functional role in PDAC cell biology and evaluated its potential as a therapeutic target in HRR-proficient PDAC. BARD1 expression was silenced in HRR- proficient PDAC cells using both small interfering RNAs and CRISPR/Cas9 deletion. Silencing BARD1 decreased cell proliferation and 3D matrigel invasion in vitro. Tumor growth of BARD1KO mouse xenografts was markedly impaired. Mechanistically, using RNA sequencing of BARD1 silenced cells, we found a de-enrichment of the epithelial-mesenchymal-transition (EMT) pathway and global downregulation of c-Myc-target genes, which control diverse cell signaling events in PDAC. BARD1 stabilized the c-Myc protein through inhibition of the ubiquitin–proteasome system. Further, to evaluate if BARD1 loss is synergistic with DNA damage agents, we employed a focused DNA damage drug library in BARD1 silenced cells and found that cells were uniquely sensitized to the PARP inhibitors class of drugs. Our proof-of-concept study implicates BARD1 as an attractive, exploitable therapeutic target for HRR proficient PDAC patients and presents a unique opportunity to expand the PDAC patient population that could benefit from PARP inhibitors in the clinical setting.
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