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Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers.

Ebi H, Faber AC, Engelman JA, Yano S - Cancer Sci. (2014)

Bottom Line: Mutations in Kirsten rat-sarcoma (KRAS) are well appreciated to be major drivers of human cancers through dysregulation of multiple growth and survival pathways.Similar to many other non-kinase oncogenes and tumor suppressors, efforts to directly target KRAS pharmaceutically have not yet materialized.Fueling these efforts is our increased understanding into the biology driving KRAS mutant cancers, in particular the important pathways that mutant KRAS governs to promote survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

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Effector proteins of Kirsten rat-sarcoma (KRAS) and apoptosis. The BCL-2 family of proteins regulates mitochondrial-driven apoptosis in KRAS mutant cancers. The BCL-2 family consists of three subfamilies: the pro-survival members such as BCL-2 or MCL1, the pro-apoptotic BCL-2 homology domain 3 (BH3)-only proteins such as BIM and PUMA, and the pro-apoptotic BAX and BCL-2 antagonist/killer (BAK; not shown in this figure). The anti-apoptotic function of oncogenic KRAS is mediated by several effector pathways that converge on the BCL-2 family of proteins. The PI3K effector pathway suppresses pro-apoptotic protein PUMA and BAX, the RAS–RAF pathway downregulates the pro-apoptotic protein BIM, and the mTORC1 pathway regulates MCL-1. In addition, the Ral-NF-κB pathway has been implicated in the regulation of BCL-XL. Thus, KRAS suppresses cell death responses through regulation of both pro-apoptotic and anti-apoptotic BCL-2 family proteins.
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fig02: Effector proteins of Kirsten rat-sarcoma (KRAS) and apoptosis. The BCL-2 family of proteins regulates mitochondrial-driven apoptosis in KRAS mutant cancers. The BCL-2 family consists of three subfamilies: the pro-survival members such as BCL-2 or MCL1, the pro-apoptotic BCL-2 homology domain 3 (BH3)-only proteins such as BIM and PUMA, and the pro-apoptotic BAX and BCL-2 antagonist/killer (BAK; not shown in this figure). The anti-apoptotic function of oncogenic KRAS is mediated by several effector pathways that converge on the BCL-2 family of proteins. The PI3K effector pathway suppresses pro-apoptotic protein PUMA and BAX, the RAS–RAF pathway downregulates the pro-apoptotic protein BIM, and the mTORC1 pathway regulates MCL-1. In addition, the Ral-NF-κB pathway has been implicated in the regulation of BCL-XL. Thus, KRAS suppresses cell death responses through regulation of both pro-apoptotic and anti-apoptotic BCL-2 family proteins.

Mentions: We have recently showed KRAS mutant colorectal cancers are particularly vulnerable to simultaneous inhibition of the BCL-2 anti-apoptotic proteins BCL-2, BCL-XL and MCL-1.44 Pure mTORC catalytic site inhibitors downregulated MCL-1 in KRAS mutant colorectal cancers, and targeting KRAS with shRNA similarly reduced mTORC1 signaling and MCL-1 levels, suggesting MCL-1 to be a vital KRAS-effector molecule in these cancers. When combined with the BCL-2/BCL-XL inhibitor navitoclax, the mTORC1/2 inhibitor AZD8055 induced tumor regressions in KRAS mutant human colorectal cancer xenografts and Kras mutant genetically engineered mouse models of colorectal cancers. In all, this study provides the rationale to use mTORC inhibitors in combination with BCL-2/BCL-XL inhibitors in KRAS mutant colorectal cancers. Altogether, these data mark the apoptotic machinery as an attractive target to treat KRAS mutant cancers (Fig.2).


Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers.

Ebi H, Faber AC, Engelman JA, Yano S - Cancer Sci. (2014)

Effector proteins of Kirsten rat-sarcoma (KRAS) and apoptosis. The BCL-2 family of proteins regulates mitochondrial-driven apoptosis in KRAS mutant cancers. The BCL-2 family consists of three subfamilies: the pro-survival members such as BCL-2 or MCL1, the pro-apoptotic BCL-2 homology domain 3 (BH3)-only proteins such as BIM and PUMA, and the pro-apoptotic BAX and BCL-2 antagonist/killer (BAK; not shown in this figure). The anti-apoptotic function of oncogenic KRAS is mediated by several effector pathways that converge on the BCL-2 family of proteins. The PI3K effector pathway suppresses pro-apoptotic protein PUMA and BAX, the RAS–RAF pathway downregulates the pro-apoptotic protein BIM, and the mTORC1 pathway regulates MCL-1. In addition, the Ral-NF-κB pathway has been implicated in the regulation of BCL-XL. Thus, KRAS suppresses cell death responses through regulation of both pro-apoptotic and anti-apoptotic BCL-2 family proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317830&req=5

fig02: Effector proteins of Kirsten rat-sarcoma (KRAS) and apoptosis. The BCL-2 family of proteins regulates mitochondrial-driven apoptosis in KRAS mutant cancers. The BCL-2 family consists of three subfamilies: the pro-survival members such as BCL-2 or MCL1, the pro-apoptotic BCL-2 homology domain 3 (BH3)-only proteins such as BIM and PUMA, and the pro-apoptotic BAX and BCL-2 antagonist/killer (BAK; not shown in this figure). The anti-apoptotic function of oncogenic KRAS is mediated by several effector pathways that converge on the BCL-2 family of proteins. The PI3K effector pathway suppresses pro-apoptotic protein PUMA and BAX, the RAS–RAF pathway downregulates the pro-apoptotic protein BIM, and the mTORC1 pathway regulates MCL-1. In addition, the Ral-NF-κB pathway has been implicated in the regulation of BCL-XL. Thus, KRAS suppresses cell death responses through regulation of both pro-apoptotic and anti-apoptotic BCL-2 family proteins.
Mentions: We have recently showed KRAS mutant colorectal cancers are particularly vulnerable to simultaneous inhibition of the BCL-2 anti-apoptotic proteins BCL-2, BCL-XL and MCL-1.44 Pure mTORC catalytic site inhibitors downregulated MCL-1 in KRAS mutant colorectal cancers, and targeting KRAS with shRNA similarly reduced mTORC1 signaling and MCL-1 levels, suggesting MCL-1 to be a vital KRAS-effector molecule in these cancers. When combined with the BCL-2/BCL-XL inhibitor navitoclax, the mTORC1/2 inhibitor AZD8055 induced tumor regressions in KRAS mutant human colorectal cancer xenografts and Kras mutant genetically engineered mouse models of colorectal cancers. In all, this study provides the rationale to use mTORC inhibitors in combination with BCL-2/BCL-XL inhibitors in KRAS mutant colorectal cancers. Altogether, these data mark the apoptotic machinery as an attractive target to treat KRAS mutant cancers (Fig.2).

Bottom Line: Mutations in Kirsten rat-sarcoma (KRAS) are well appreciated to be major drivers of human cancers through dysregulation of multiple growth and survival pathways.Similar to many other non-kinase oncogenes and tumor suppressors, efforts to directly target KRAS pharmaceutically have not yet materialized.Fueling these efforts is our increased understanding into the biology driving KRAS mutant cancers, in particular the important pathways that mutant KRAS governs to promote survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

Show MeSH
Related in: MedlinePlus