EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

被引：308

作者：

Amodio, Vito ^{[1
,2
]}

Yaeger, Rona ^{[3
]}

Arcella, Pamela ^{[1
,2
]}

Cancelliere, Carlotta ^{[1
]}

Lamba, Simona ^{[1
]}

Lorenzato, Annalisa ^{[1
,2
]}

Arena, Sabrina ^{[1
,2
]}

Montone, Monica ^{[1
]}

Mussolin, Benedetta ^{[1
]}

Bian, Yu ^{[4
]}

Whaley, Adele ^{[4
]}

Pinnelli, Marika ^{[1
,2
]}

Murciano-Goroff, Yonina R. ^{[3
]}

Vakiani, Efsevia ^{[5
]}

Valeri, Nicola ^{[6
,7
]}

Liao, Wei-Li ^{[8
]}

Bhalkikar, Anuja ^{[8
]}

Thyparambil, Sheeno ^{[8
]}

Zhao, Hui-Yong ^{[4
,9
]}

de Stanchina, Elisa ^{[4
,9
]}

Marsoni, Silvia ^{[10
,11
]}

Siena, Salvatore ^{[10
,12
]}

Bertotti, Andrea ^{[1
,2
]}

Trusolino, Livio ^{[1
,2
]}

Li, Bob T. ^{[3
,13
]}

Rosen, Neal ^{[1
,14
]}

Di Nicolantonio, Federica ^{[1
,2
]}

Bardelli, Alberto ^{[1
,2
]}

Misale, Sandra ^{[4
]}

机构：

[1] Candiolo Canc Inst, FPO IRCCS, Turin, Italy

[2] Univ Torino, Dept Oncol, Turin, Italy

[3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[6] Inst Canc Res, Ctr Evolut & Canc, London, England

[7] Royal Marsden Hosp, Dept Med, London, England

[8] mProbe Inc, Rockville, MD USA

[9] Mem Sloan Kettering Canc Ctr, Antitumour Assessment Core Facil, New York, NY 10065 USA

[10] Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Milan, Italy

[11] Inst FIRC Oncol Mol IFOM, Milan, Italy

[12] Univ Milan, Dept Oncol & Hematooncol, Milan, Italy

[13] Weill Cornell Med Coll, New York, NY USA

[14] Mem Sloan Kettering Canc Ctr, Ctr Mol Based Therapy, New York, NY 10065 USA

来源：

CANCER DISCOVERY | 2020年 / 10卷 / 08期

基金：

欧洲研究理事会;

关键词：

ACQUIRED-RESISTANCE; LANDSCAPE; CETUXIMAB; TRIAL; RAS;

D O I：

10.1158/2159-8290.CD-20-0187

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Most patients with KRAS(G12C)-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS(G12C) inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRAS(G12C) inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS(G12C) colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS(G12C) colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRAS(G12C) inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRAS(G12C) blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRAS(G12C) inhibitors. The combinatorial targeting of EGFR and KRAS(G12C) is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS(G12C) colorectal cancer. SIGNIFICANCE: The efficacy of KRAS(G12C)inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRAS(G12C) inhibition in colorectal cancer. EGFR and KRAS(G12C) should be concomitantly inhibited to overcome resistance to KRAS(G12C) blockade in colorectal tumors.

引用

页码：1129 / 1139

页数：11

共 39 条

[1] The genomic landscape of response to EGFR blockade in colorectal cancer
Bertotti, Andrea
Papp, Eniko
Jones, Sian
Adleff, Vilmos
Anagnostou, Valsamo
Lupo, Barbara
Sausen, Mark
Phallen, Jillian
Hruban, Carolyn A.
Tokheim, Collin
Niknafs, Noushin
Nesselbush, Monica
Lytle, Karli
Sassi, Francesco
Cottino, Francesca
Migliardi, Giorgia
Zanella, Eugenia R.
Ribero, Dario
Russolillo, Nadia
Mellano, Alfredo
Muratore, Andrea
Paraluppi, Gianluca
Salizzoni, Mauro
Marsoni, Silvia
Kragh, Michael
Lantto, Johan
Cassingena, Andrea
Li, Qing Kay
Karchin, Rachel
Scharpf, Robert
Sartore-Bianchi, Andrea
Siena, Salvatore
Diaz, Luis A., Jr.
Trusolino, Livio
Velculescu, Victor E.
[J]. NATURE, 2015, 526 (7572) : 263 - +
[2] A Molecularly Annotated Platform of Patient-Derived Xenografts ("Xenopatients") Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer
Bertotti, Andrea
Migliardi, Giorgia
Galimi, Francesco
Sassi, Francesco
Torti, Davide
Isella, Claudio
Cora, Davide
Di Nicolantonio, Federica
Buscarino, Michela
Petti, Consalvo
Ribero, Dario
Russolillo, Nadia
Muratore, Andrea
Massucco, Paolo
Pisacane, Alberto
Molinaro, Luca
Valtorta, Emanuele
Sartore-Bianchi, Andrea
Risio, Mauro
Capussotti, Lorenzo
Gambacorta, Marcello
Siena, Salvatore
Medico, Enzo
Sapino, Anna
Marsoni, Silvia
Comoglio, Paolo M.
Bardelli, Alberto
Trusolino, Livio
[J]. CANCER DISCOVERY, 2011, 1 (06) : 508 - 523
[3] GEFs and GAPs: Critical elements in the control of small G proteins
Bos, Johannes L.
Rehmann, Holger
Wittinghofer, Alfred
[J]. CELL, 2007, 129 (05) : 865 - 877
[4] The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
Canon, Jude
Rex, Karen
Saiki, Anne Y.
Mohr, Christopher
Cooke, Keegan
Bagal, Dhanashri
Gaida, Kevin
Holt, Tyler
Knutson, Charles G.
Koppada, Neelima
Lanman, Brian A.
Werner, Jonathan
Rapaport, Aaron S.
San Miguel, Tisha
Ortiz, Roberto
Osgood, Tao
Sun, Ji-Rong
Zhu, Xiaochun
McCarter, John D.
Volak, Laurie P.
Houk, Brett E.
Fakih, Marwan G.
O'Neil, Bert H.
Price, Timothy J.
Falchook, Gerald S.
Desai, Jayesh
Kuo, James
Govindan, Ramaswamy
Hong, David S.
Ouyang, Wenjun
Henary, Haby
Arvedson, Tara
Cee, Victor J.
Lipford, J. Russell
[J]. NATURE, 2019, 575 (7781) : 217 - +
[5] Absolute Quantitation of Met Using Mass Spectrometry for Clinical Application: Assay Precision, Stability, and Correlation with MET Gene Amplification in FFPE Tumor Tissue
Catenacci, Daniel V. T.
Liao, Wei-Li
Thyparambil, Sheeno
Henderson, Les
Xu, Peng
Zhao, Lei
Rambo, Brittany
Hart, John
Xiao, Shu-Yuan
Bengali, Kathleen
Uzzell, Jamar
Darfler, Marlene
Krizman, David B.
Cecchi, Fabiola
Bottaro, Donald P.
Karrison, Theodore
Veenstra, Timothy D.
Hembrough, Todd
Burrows, Jon
[J]. PLOS ONE, 2014, 9 (07):
[6] Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry
Chung, KY
Shia, J
Kemeny, NE
Shah, M
Schwartz, GK
Tse, A
Hamilton, A
Pan, D
Schrag, D
Schwartz, L
Klimstra, DS
Fridman, D
Kelsen, DP
Saltz, LB
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (09) : 1803 - 1810
[7] EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib
Corcoran, Ryan B.
Ebi, Hiromichi
Turke, Alexa B.
Coffee, Erin M.
Nishino, Michiya
Cogdill, Alexandria P.
Brown, Ronald D.
Della Pelle, Patricia
Dias-Santagata, Dora
Hung, Kenneth E.
Flaherty, Keith T.
Piris, Adriano
Wargo, Jennifer A.
Settleman, Jeffrey
Mino-Kenudson, Mari
Engelman, Jeffrey A.
[J]. CANCER DISCOVERY, 2012, 2 (03) : 227 - 235
[8] Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer
De Robertis, Mariangela
Loiacono, Luisa
Fusilli, Caterina
Poeta, Maria Luana
Mazza, Tommaso
Sanchez, Massimo
Marchionni, Luigi
Signori, Emanuela
Lamorte, Giuseppe
Vescovi, Angelo Luigi
Garcia-Foncillas, Jesus
Fazio, Vito Michele
[J]. CLINICAL CANCER RESEARCH, 2017, 23 (01) : 159 - 170
[9] Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses
Di Nicolantonio, Federica
Arena, Sabrina
Gallicchio, Margherita
Zecchin, Davide
Martini, Miriam
Flonta, Simona Emilia
Stella, Giulia Maria
Lamba, Simona
Cancelliere, Carlotta
Russo, Mariangela
Geuna, Massimo
Appendino, Giovanni
Fantozzi, Roberto
Medico, Enzo
Bardelli, Alberto
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (52) : 20864 - 20869
[10] The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers
Diaz, Luis A., Jr.
Williams, Richard T.
Wu, Jian
Kinde, Isaac
Hecht, J. Randolph
Berlin, Jordan
Allen, Benjamin
Bozic, Ivana
Reiter, Johannes G.
Nowak, Martin A.
Kinzler, Kenneth W.
Oliner, Kelly S.
Vogelstein, Bert
[J]. NATURE, 2012, 486 (7404) : 537 - 540

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