Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer

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Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. / Hobbs, G. Aaron; Baker, Nicole M.; Miermont, Anne M.; Thurman, Ryan D.; Pierobon, Mariaelena; Tran, Timothy H.; Anderson, Andrew O.; Waters, Andrew M.; Diehl, J. Nathaniel; Papke, Bjoern; Hodge, Richard G.; Klomp, Jennifer E.; Goodwin, Craig M.; DeLiberty, Jonathan M.; Wang, Junning; Ng, Raymond W.S.; Gautam, Prson; Bryant, Kirsten L.; Esposito, Dominic; Campbell, Sharon L.; Petricoin, Emanuel F.; Simanshu, Dhirendra K.; Aguirre, Andrew J.; Wolpin, Brian M.; Wennerberg, Krister; Rudloff, Udo; Cox, Adrienne D.; Der, Channing J.

In: Cancer Discovery, Vol. 10, No. 1, 2020, p. 104-123.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hobbs, GA, Baker, NM, Miermont, AM, Thurman, RD, Pierobon, M, Tran, TH, Anderson, AO, Waters, AM, Diehl, JN, Papke, B, Hodge, RG, Klomp, JE, Goodwin, CM, DeLiberty, JM, Wang, J, Ng, RWS, Gautam, P, Bryant, KL, Esposito, D, Campbell, SL, Petricoin, EF, Simanshu, DK, Aguirre, AJ, Wolpin, BM, Wennerberg, K, Rudloff, U, Cox, AD & Der, CJ 2020, 'Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer', Cancer Discovery, vol. 10, no. 1, pp. 104-123. https://doi.org/10.1158/2159-8290.CD-19-1006

APA

Hobbs, G. A., Baker, N. M., Miermont, A. M., Thurman, R. D., Pierobon, M., Tran, T. H., Anderson, A. O., Waters, A. M., Diehl, J. N., Papke, B., Hodge, R. G., Klomp, J. E., Goodwin, C. M., DeLiberty, J. M., Wang, J., Ng, R. W. S., Gautam, P., Bryant, K. L., Esposito, D., ... Der, C. J. (2020). Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discovery, 10(1), 104-123. https://doi.org/10.1158/2159-8290.CD-19-1006

Vancouver

Hobbs GA, Baker NM, Miermont AM, Thurman RD, Pierobon M, Tran TH et al. Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discovery. 2020;10(1):104-123. https://doi.org/10.1158/2159-8290.CD-19-1006

Author

Hobbs, G. Aaron ; Baker, Nicole M. ; Miermont, Anne M. ; Thurman, Ryan D. ; Pierobon, Mariaelena ; Tran, Timothy H. ; Anderson, Andrew O. ; Waters, Andrew M. ; Diehl, J. Nathaniel ; Papke, Bjoern ; Hodge, Richard G. ; Klomp, Jennifer E. ; Goodwin, Craig M. ; DeLiberty, Jonathan M. ; Wang, Junning ; Ng, Raymond W.S. ; Gautam, Prson ; Bryant, Kirsten L. ; Esposito, Dominic ; Campbell, Sharon L. ; Petricoin, Emanuel F. ; Simanshu, Dhirendra K. ; Aguirre, Andrew J. ; Wolpin, Brian M. ; Wennerberg, Krister ; Rudloff, Udo ; Cox, Adrienne D. ; Der, Channing J. / Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. In: Cancer Discovery. 2020 ; Vol. 10, No. 1. pp. 104-123.

Bibtex

@article{d60e2c2d612f4530a323bd897c66a813,
title = "Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer",
abstract = "Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (~1%) in lung and colorectal cancers, yet relatively common (~20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specifi c properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D - or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V - but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this defi ciency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.",
author = "Hobbs, {G. Aaron} and Baker, {Nicole M.} and Miermont, {Anne M.} and Thurman, {Ryan D.} and Mariaelena Pierobon and Tran, {Timothy H.} and Anderson, {Andrew O.} and Waters, {Andrew M.} and Diehl, {J. Nathaniel} and Bjoern Papke and Hodge, {Richard G.} and Klomp, {Jennifer E.} and Goodwin, {Craig M.} and DeLiberty, {Jonathan M.} and Junning Wang and Ng, {Raymond W.S.} and Prson Gautam and Bryant, {Kirsten L.} and Dominic Esposito and Campbell, {Sharon L.} and Petricoin, {Emanuel F.} and Simanshu, {Dhirendra K.} and Aguirre, {Andrew J.} and Wolpin, {Brian M.} and Krister Wennerberg and Udo Rudloff and Cox, {Adrienne D.} and Der, {Channing J.}",
year = "2020",
doi = "10.1158/2159-8290.CD-19-1006",
language = "English",
volume = "10",
pages = "104--123",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research",
number = "1",

}

RIS

TY - JOUR

T1 - Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer

AU - Hobbs, G. Aaron

AU - Baker, Nicole M.

AU - Miermont, Anne M.

AU - Thurman, Ryan D.

AU - Pierobon, Mariaelena

AU - Tran, Timothy H.

AU - Anderson, Andrew O.

AU - Waters, Andrew M.

AU - Diehl, J. Nathaniel

AU - Papke, Bjoern

AU - Hodge, Richard G.

AU - Klomp, Jennifer E.

AU - Goodwin, Craig M.

AU - DeLiberty, Jonathan M.

AU - Wang, Junning

AU - Ng, Raymond W.S.

AU - Gautam, Prson

AU - Bryant, Kirsten L.

AU - Esposito, Dominic

AU - Campbell, Sharon L.

AU - Petricoin, Emanuel F.

AU - Simanshu, Dhirendra K.

AU - Aguirre, Andrew J.

AU - Wolpin, Brian M.

AU - Wennerberg, Krister

AU - Rudloff, Udo

AU - Cox, Adrienne D.

AU - Der, Channing J.

PY - 2020

Y1 - 2020

N2 - Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (~1%) in lung and colorectal cancers, yet relatively common (~20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specifi c properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D - or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V - but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this defi ciency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.

AB - Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (~1%) in lung and colorectal cancers, yet relatively common (~20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specifi c properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D - or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V - but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this defi ciency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.

U2 - 10.1158/2159-8290.CD-19-1006

DO - 10.1158/2159-8290.CD-19-1006

M3 - Journal article

C2 - 31649109

AN - SCOPUS:85077760989

VL - 10

SP - 104

EP - 123

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 1

ER -

ID: 256940716