Clinical Activity of Mitogen-Activated Protein Kinase Inhibitors in Patients With MAP2K1 (MEK1)-Mutated Metastatic Cancers

被引：0

作者：

Dankner, Matthew ^{[1
,2
,3
,4
]}

Rousselle, Emmanuelle ^{[2
,3
,5
]}

Petrecca, Sarah ^{[1
]}

Fabi, Francois ^{[1
]}

Nowakowski, Alexander ^{[1
,4
]}

Lazaratos, Anna-Maria ^{[4
]}

Rajadurai, Charles Vincent ^{[1
,2
,3
]}

Stein, Andrew J. B. ^{[1
]}

Bian, David ^{[1
]}

Tai, Peter ^{[1
]}

Belaiche, Alicia ^{[1
]}

Li, Meredith ^{[1
,2
,3
]}

Quaiattini, Andrea ^{[6
]}

Normanno, Nicola ^{[7
]}

Arcila, Maria ^{[8
]}

Elkrief, Arielle ^{[8
,9
]}

Johnson, Douglas B. ^{[10
]}

Ladanyi, Marc ^{[8
]}

Rose, April A. N. ^{[1
,2
,3
,5
,11
]}

机构：

[1] McGill Univ, Fac Med, Montreal, PQ, Canada

[2] Jewish Gen Hosp, Lady Davis Res Inst, Montreal, PQ, Canada

[3] Jewish Gen Hosp, Segal Canc Ctr, Montreal, PQ, Canada

[4] Rosalind & Morris Goodman Canc Inst, Montreal, PQ, Canada

[5] McGill Univ, Fac Med, Div Expt Med, Montreal, PQ, Canada

[6] McGill Univ, Schulich Lib Phys Sci Life Sci & Engn, Montreal, PQ, Canada

[7] IRCCS Ist Romagnolo Studio Tumori IRST Dino Amador, Meldola, FC, Italy

[8] Mem Sloan Kettering Canc Ctr, New York, NY USA

[9] Ctr Hosp Univ Montreal CHUM, Montreal, PQ, Canada

[10] Vanderbilt Univ, Med Ctr, Nashville, TN USA

[11] McGill Univ, Gerald Bronfman Dept Oncol, Montreal, PQ, Canada

来源：

JCO PRECISION ONCOLOGY | 2025年 / 9卷

关键词：

ACQUIRED-RESISTANCE; RAF INHIBITION; MUTATIONS; BRAF; LANDSCAPE; MEK; PATHWAY; COMBINATIONS;

D O I：

10.1200/PO.24.00199

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PURPOSE MAP2K1/MEK1 mutations are potentially actionable drivers in cancer. MAP2K1 mutations have been functionally classified into three groups according to their dependency on upstream RAS/RAF signaling. However, the clinical efficacy of mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) for MAP2K1-mutant tumors is not well defined. We sought to characterize the genomic and clinical landscape of MAP2K1 mutant tumors to evaluate the relationship between MAP2K1 mutation class and clinical activity of MAPKi. METHODS We interrogated American Association for Cancer Research (AACR) GENIE (v13) to analyze solid tumors with MAP2K1 mutations. We performed a systematic review and meta-analysis of published reports of patients with MAP2K1-mutant cancers treated with MAPKi according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary end point was progression-free survival (PFS), and secondary end points were overall treatment response rate (ORR), duration of response (DOR), and overall survival. RESULTS In the AACR GENIE data set, class 2 MAP2K1 mutations (63%) were more prevalent than class 1 (24%) and class 3 (13%) mutations (P < .0001). Co-occurring MAPK pathway-activating mutations were more likely to occur in class 1 versus class 2 or 3 MAP2K1-mutant tumors (P < .0001). Our systematic meta-analysis of the literature identified 46 patients with MAP2K1-mutant tumors who received MAPKi. In these patients, ORR was 28% and median PFS was 3.9 months. ORR did not differ according to MAP2K1 mutation class or cancer type. However, patients with class 2 mutations experienced longer PFS (5.0 months) and DOR (23.8 months) compared with patients with class 1, 3, or unclassified MAP2K1 mutations (PFS 3.5 months, P = .04; DOR 4.2 months, P = .02). CONCLUSION Patients with class 2 MAP2K1 mutations represent a novel subgroup that may derive benefit from MAPKi. Prospective clinical studies with novel MAPKi regimens are warranted in these patients.

引用

页数：18

共 46 条

[1] Genomic Classification of Cutaneous Melanoma [J].

Akbani, Rehan ;

Akdemir, Kadir C. ;

Aksoy, B. Arman ;

Albert, Monique ;

Ally, Adrian ;

Amin, Samirkumar B. ;

Arachchi, Harindra ;

Arora, Arshi ;

Auman, J. Todd ;

Ayala, Brenda ;

Baboud, Julien ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barnabas, Nandita ;

Bartlett, John ;

Bartlett, Pam ;

Bastian, Boris C. ;

Baylin, Stephen B. ;

Behera, Madhusmita ;

Belyaev, Dmitry ;

Benz, Christopher ;

Bernard, Brady ;

Beroukhim, Rameen ;

Bir, Natalie ;

Black, Aaron D. ;

Bodenheimer, Tom ;

Boice, Lori ;

Boland, Genevieve M. ;

Bono, Riccardo ;

Bootwalla, Moiz S. ;

Bosenberg, Marcus ;

Bowen, Jay ;

Bowlby, Reanne ;

Bristow, Christopher A. ;

Brockway-Lunardi, Laura ;

Brooks, Denise ;

Brzezinski, Jakub ;

Bshara, Wiam ;

Buda, Elizabeth ;

Burns, William R. ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Calderone, Tiffany ;

Cappellini, Giancarlo Antonini ;

Carter, Candace ;

Carter, Scott L. ;

Cherney, Lynn ;

Cherniack, Andrew D. ;

Chevalier, Aaron ;

Chin, Lynda .

CELL, 2015, 161 (07) :1681-1696

[2] BRAF and MAP2K1 mutations in Langerhans cell histiocytosis: a study of 50 cases [J].

Alayed, Khaled ;

Medeiros, L. Jeffrey ;

Patel, Keyur P. ;

Zuo, Zhuang ;

Li, Shaoying ;

Verma, Shalini ;

Galbincea, John ;

Cason, R. Craig ;

Luthra, Rajyalakshmi ;

Yin, C. Cameron .

HUMAN PATHOLOGY, 2016, 52 :61-67

[3] AACR Project GENIE: Powering Precision Medicine through an International Consortium [J].

Andre, Fabrice ;

Arnedos, Monica ;

Baras, Alexander S. ;

Baselga, Jose ;

Bedard, Philippe L. ;

Berger, Michael F. ;

Bierkens, Mariska ;

Calvo, Fabien ;

Cerami, Ethan ;

Chakravarty, Debyani ;

Dang, Kristen K. ;

Davidson, Nancy E. ;

Del Vecchio, Fitz Catherine ;

Dogan, Semih ;

DuBois, Raymond N. ;

Ducar, Matthew D. ;

Futreal, P. Andrew ;

Gao Jianjiong ;

Garcia, Francisco ;

Gardos, Stu ;

Gocke, Christopher D. ;

Gross, Benjamin E. ;

Guinney, Justin ;

Heins, Zachary J. ;

Hintzen, Stephanie ;

Horlings, Hugo ;

Hudecek, Jan ;

Hyman, David M. ;

Kamel-Reid, Suzanne ;

Kandoth, Cyriac ;

Kinyua, Walter ;

Kumari, Priti ;

Kundra, Ritika ;

Ladanyi, Marc ;

Lefebvre, Celine ;

LeNoue-Newton, Michele L. ;

Lepisto, Eva M. ;

Levy, Mia A. ;

Lindeman, Neal, I ;

Lindsay, James ;

Liu, David ;

Lu Zhibin ;

MacConaill, Laura E. ;

Ian, Maurer ;

Maxwell, David S. ;

Meijer, Gerrit A. ;

Meric-Bernstam, Funda ;

Micheel, Christine M. ;

Miller, Clinton ;

Mills, Gordon .

CANCER DISCOVERY, 2017, 7 (08) :818-831

[4] MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking [J].

Arcila, Maria E. ;

Drilon, Alexander ;

Sylvester, Brooke E. ;

Lovly, Christine M. ;

Borsu, Laetitia ;

Reva, Boris ;

Kris, Mark G. ;

Solit, David B. ;

Ladanyi, Marc .

CLINICAL CANCER RESEARCH, 2015, 21 (08) :1935-1943

[5] Acquired Resistance to KRASG12C Inhibition in Cancer [J].

Awad, M. M. ;

Liu, S. ;

Rybkin, I. I. ;

Arbour, K. C. ;

Dilly, J. ;

Zhu, V. W. ;

Johnson, M. L. ;

Heist, R. S. ;

Patil, T. ;

Riely, G. J. ;

Jacobson, J. O. ;

Yang, X. ;

Persky, N. S. ;

Root, D. E. ;

Lowder, K. E. ;

Feng, H. ;

Zhang, S. S. ;

Haigis, K. M. ;

Hung, Y. P. ;

Sholl, L. M. ;

Wolpin, B. M. ;

Wiese, J. ;

Christiansen, J. ;

Lee, J. ;

Schrock, A. B. ;

Lim, L. P. ;

Garg, K. ;

Li, M. ;

Engstrom, L. D. ;

Waters, L. ;

Lawson, J. D. ;

Olson, P. ;

Lito, P. ;

Ou, S. -H. I. ;

Christensen, J. G. ;

Janne, P. A. ;

Aguirre, A. J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2021, 384 (25) :2382-2393

[6] The genomic landscape of response to EGFR blockade in colorectal cancer [J].

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. .

NATURE, 2015, 526 (7572) :263-+

[7] Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions [J].

Brannon, A. Rose ;

Vakiani, Efsevia ;

Sylvester, Brooke E. ;

Scott, Sasinya N. ;

McDermott, Gregory ;

Shah, Ronak H. ;

Kania, Krishan ;

Viale, Agnes ;

Oschwald, Dayna M. ;

Vacic, Vladimir ;

Emde, Anne-Katrin ;

Cercek, Andrea ;

Yaeger, Rona ;

Kemeny, Nancy E. ;

Saltz, Leonard B. ;

Shia, Jinru ;

D'Angelica, Michael I. ;

Weiser, Martin R. ;

Solit, David B. ;

Berger, Michael F. .

GENOME BIOLOGY, 2014, 15 (08)

[8] Preexisting MEK1P124 Mutations Diminish Response to BRAF Inhibitors in Metastatic Melanoma Patients [J].

Carlino, Matteo S. ;

Fung, Carina ;

Shahheydari, Hamideh ;

Todd, Jason R. ;

Boyd, Suzanah C. ;

Irvine, Mal ;

Nagrial, Adnan M. ;

Scolyer, Richard A. ;

Kefford, Richard F. ;

Long, Georgina V. ;

Rizos, Helen .

CLINICAL CANCER RESEARCH, 2015, 21 (01) :98-105

[9] Oncogenic MAP2K1 mutations in human epithelial tumors [J].

Choi, Young Lim ;

Soda, Manabu ;

Ueno, Toshihide ;

Hamada, Toru ;

Haruta, Hidenori ;

Yamato, Azusa ;

Fukumura, Kazutaka ;

Ando, Mizuo ;

Kawazu, Masahito ;

Yamashita, Yoshihiro ;

Mano, Hiroyuki .

CARCINOGENESIS, 2012, 33 (05) :956-961

[10] EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib [J].

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. .

CANCER DISCOVERY, 2012, 2 (03) :227-235

← 1 2 3 4 5 →