Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers

Ebi, Hiromichi; Corcoran, Ryan B.; Singh, Anurag; Chen, Zhao; Song, Youngchul; Lifshits, Eugene; Ryan, David P.; Meyerhardt, Jeffrey A.; Benes, Cyril H.; Settleman, Jeffrey; Wong, Kwok-Kin; Cantley, Lewis C.; Engelman, Jeffrey A.

doi:10.1172/jci57909

Cited by 182 publications

(190 citation statements)

References 54 publications

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“…This is consistent with a recent report showing that in K-Ras mutant colorectal lines, PI3K pathway activity is driven by receptor tyrosine kinase rather than mutant K-Ras signaling (39). Furthermore, we show for the first time that selective ERK inhibitors can overcome this resistance and thus that ERK inhibition may constitute a therapeutic option for treating patients who have progressed on MEK inhibitor therapy and show reactivation of MAPK signaling.…”

Section: Discussionsupporting

confidence: 93%

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Hatzivassiliou¹,

Liu²,

O’Brien³

et al. 2012

Molecular Cancer Therapeutics

189

155

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The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/ extracellular signal-regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant cell lines retained their addiction to the mitogenactivated protein kinase (MAPK) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERK1/2 kinases. These data suggest that tumors with acquired MEK inhibitor resistance remain dependent on the MAPK pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEK target. Importantly, we show that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to both inhibit the emergence of resistance, as well as to overcome acquired resistance to MEK inhibitors. Therefore, our data provide a rationale for cotargeting multiple nodes within the MAPK signaling cascade in K-ras mutant tumors to maximize therapeutic benefit for patients.

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Section: Discussionsupporting

confidence: 93%

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Hatzivassiliou¹,

Liu²,

O’Brien³

et al. 2012

Molecular Cancer Therapeutics

189

155

View full text Add to dashboard Cite

show abstract

“…10). Although challenging the signalling dogma holding that the GTPase-dependent stimulation of PI3Ka is mostly mediated by direct physical interactions with oncogenic Ras proteins 33 , these results are consistent with previous data indicating that the PI3Ka/Akt axis can be activated in Ras-independent manners in some Ras-transformed cells 16,24,[34][35][36][37] . Interestingly, the influence of R-Ras2 on the PI3K/Akt pathway is highly dependent on the experimental conditions used.…”

Section: R-ras2 Deficient Tumours Develop Compensatory Mechanismssupporting

confidence: 91%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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R-Ras2 is a transforming GTPase that shares downstream effectors with Ras subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss-and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contrast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.

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“…High levels of autocrine NRG1 stimulation of ERBB2-ERBB3-PI3K signaling has been shown to underlie sensitivity to the HER2 kinase inhibitor lapatinib in a subset of cell lines, whereas inhibition of EGFR-ERBB3-driven PI3K activity has been related to the effi cacy of the EGFR inhibitor gefi tinib and others ( 19 , 30 ). Interestingly, RTK-driven PI3K activity has been shown to be important for growth and survival even in the context of KRAS -mutant colorectal cancer cells, though no relationship to EMT was described ( 32 ). Our data support and expand on this fi nding, as the cell lines tested in this study harbor mutations in KRAS , but still remain dependent on ERBB3 for PI3K signaling before EMT.…”

Section: Discussionsupporting

confidence: 79%

Epithelial-to-Mesenchymal Transition Rewires the Molecular Path to PI3K-Dependent Proliferation

2014

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Tumors showing evidence of epithelial-to-mesenchymal transition (EMT) have been associated with metastasis, drug resistance, and poor prognosis. Heterogeneity along the EMT spectrum is observed between and within tumors. To develop effective therapeutics, a mechanistic understanding of how EMT affects the molecular requirements for proliferation is needed. We found that although cells use phosphoinositide 3-kinase (PI3K) for proliferation in both the epithelial and mesenchymal states, EMT rewires the mechanism of PI3K pathway activation. In epithelial cells, autocrine ERBB3 activation maintains PI3K signaling, whereas after EMT, downregulation of ERBB3 disrupts autocrine signaling to PI3K. Loss of ERBB3 leads to reduced serum-independent proliferation after EMT that can be rescued through reactivation of PI3K by enhanced signaling from p110α, ERBB3 reexpression, or growth factor stimulation. In vivo , we demonstrate that PIK3CA expression is upregulated in mesenchymal tumors with low levels of ERBB3 . This study defi nes how ERBB3 downregulation after EMT affects PI3K-dependent proliferation. SIGNIFICANCE:This study describes a mechanism through which EMT transition alters the proliferative potential of cells by modulating ERBB3 expression. Furthermore, it demonstrates the potential for multiple molecular routes to drive proliferation in different cell states, illustrating how changes in EMT status can rewire signaling upstream of cell proliferation. Cancer Discov; 4(2);

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Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers

Cited by 182 publications

References 54 publications

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Epithelial-to-Mesenchymal Transition Rewires the Molecular Path to PI3K-Dependent Proliferation

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