The ERBB network facilitates KRAS-driven lung tumorigenesis

Kruspig, Björn; Monteverde, Tiziana; Neidler, Sarah; Höck, A.; Kerr, Emma; Nixon, Colin; Clark, William; Hedley, Ann; Laing, Sarah; Coffelt, Seth B.; Quesne, John Le; Dick, Craig; Vousden, Karen H.; Martins, Carla P.; Murphy, Daniel J.

doi:10.1126/scitranslmed.aao2565

Cited by 90 publications

(86 citation statements)

References 45 publications

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“…2D). Moreover, we observed increased protein levels of total RAS in RAS mutant organoids, indicative of positive feedback regulation induced by oncogenic RAS proteins as previously reported [53][54][55] .…”

Section: Generation Of Endogenous Oncogenic Ras and Braf Knock-in Varsupporting

confidence: 88%

Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

Hami

Lohuis

et al. 2019

Preprint

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Colorectal cancers (CRCs) with oncogenic mutations in RAS and BRAF are associated with anti-EGFR therapy resistance. Consequently, all RAS mutant CRC patients are being excluded from this therapy. However, heterogeneity in drug response has been reported between RAS mutant CRC patients. It is poorly understood to what extent such differences are derived from different genetic backgrounds or intrinsic differences between the various RAS pathway mutations. Therefore, using CRISPR technology we generated an isogenic panel of patientderived CRC organoids with various RAS pathway mutations (i.e. KRAS G12D , BRAF V600E , KRAS G13D and NRAS G12D ). All RAS pathway mutants promote ERK activation and tumor growth. However, KRAS G12D and BRAF V600E mutations in particular conferred robust resistance to anti-EGFR therapy, both in vitro and in vivo. Moreover, untreated KRAS G13D mutants showed fastest growth in mice but remained sensitive to anti-EGFR therapy. Together, introducing mutationspecific oncogene signaling in CRC organoids resembles clinical phenotypes and improves understanding of genotype-phenotype correlations.

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Section: Generation Of Endogenous Oncogenic Ras and Braf Knock-in Varsupporting

confidence: 88%

Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

Hami

Lohuis

et al. 2019

Preprint

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“…In both types of tumor cell neratinib reduced the expression of K-RAS. Others have also recently shown that neratinib and afatinib in solid tumor cell lines can reduce ERBB1/2/3 expression [24,25].…”

Section: Discussionmentioning

confidence: 96%

Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells

et al. 2019

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Prior studies demonstrated that the irreversible ERBB1/2/4 inhibitor neratinib caused plasma membrane-associated mutant K-RAS to localize in intracellular vesicles, concomitant with its degradation. Herein, we discovered that neratinib interacted with the chemically distinct irreversible ERBB1/2/4 inhibitor afatinib to reduce expression of ERBB1, ERBB2, K-RAS and N-RAS; this was associated with greater-than-additive cell killing of pancreatic tumor cells. Knock down of Beclin1, ATG16L1, Rubicon or cathepsin B significantly lowered the ability of neratinib to reduce ERBB1 and K-RAS expression, and to cause tumor cell death. Knock down of ATM-AMPK suppressed vesicle formation and knock down of cathepsin B-AIF significantly reduced neratinib lethality. PKG phosphorylates K-RAS and HMG CoA reductase inhibitors reduce K-RAS farnesylation both of which remove K-RAS from the plasma membrane, abolishing its activity. Neratinib interacted with the PKG activator sildenafil and the HMG CoA reductase inhibitor atorvastatin to further reduce K-RAS expression, and to further enhance cell killing. Neratinib is also a Ste20 kinase family inhibitor and in carcinoma cells, and hematopoietic cancer cells lacking ERBB1/2/4, it reduced K-RAS expression and the phosphorylation of MST1/3/4/ Ezrin by ~30%. Neratinib increased LATS1 phosphorylation as well as that of YAP and TAZ also by ~30%, caused the majority of YAP to translocate into the cytosol and reduced YAP/TAZ #

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“…Inhibition of single downstream effector molecules (e.g., RAF, MEK, or PI3K) did not produce major clinical benefits, where induction of compensatory mechanisms that reactivate the pathway or even activation of alternative KRAS signaling effectors may account for resistance mechanisms [10,11]. Nevertheless, since mutant KRAS cells seem to show increased dependence on receptor tyrosine kinase (RTK) signaling such as erythroblastic leukemia viral oncogene (ERBB) family, hepatocyte growth factor receptor (MET) and insulin growth factor receptor (IGFR), combined inhibition of specific signaling effectors and RTK (e.g., MEK and IGFR inhibition, or MEK and pan-ERBB inhibitors) have shown therapeutic potential [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

Carvalho

Machado

Martins

et al. 2019

Cancers

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Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens.

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The ERBB network facilitates KRAS-driven lung tumorigenesis

Cited by 90 publications

References 45 publications

Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

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