Mechanisms of Response and Tolerance to Active RAS Inhibition in KRAS-Mutant Non-Small Cell Lung Cancer

被引：17

作者：

Araujo, Haniel A. ^{[1
]}

Pechuan-Jorge, Ximo ^{[2
]}

Zhou, Teng ^{[1
]}

Do, Minh Truong ^{[1
]}

Hu, Xin ^{[1
]}

Alvarez, Frank R. Rojas ^{[3
]}

Salvatierra, Maria E. ^{[3
]}

Ibarguen, Heladio P. ^{[3
]}

Lee, Richard ^{[1
]}

Raghulan, Rashi ^{[2
]}

Shah, Harshit ^{[2
]}

Ayala, Mariela A. Moreno ^{[2
]}

Chen, Kevin ^{[2
]}

Shifrin, Nataliya Tovbis ^{[2
]}

Wu, Shuhong ^{[4
]}

Soto, Luisa M. Solis ^{[3
]}

Negrao, Marcelo V. ^{[1
]}

Gibbons, Don L. ^{[1
]}

Hong, David S. ^{[1
]}

Roth, Jack A. ^{[4
]}

Heymach, John V. ^{[1
]}

Zhang, Jianjun ^{[1
]}

Jiang, Jingjing ^{[2
]}

Singh, Mallika ^{[2
]}

Smith, Jacqueline A. M. ^{[2
]}

Quintana, Elsa ^{[2
]}

Skoulidis, Ferdinandos ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[2] Revolut Med, Redwood City, CA USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX USA

来源：

CANCER DISCOVERY | 2024年 / 14卷 / 11期

关键词：

FEEDBACK ACTIVATION; GENE-EXPRESSION; SOLID TUMORS; ADENOCARCINOMA; ANGIOGENESIS; SUPPRESSION; RESISTANCE; EMERGENCE;

D O I：

10.1158/2159-8290.CD-24-0421

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histologic features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.Significance: Our work reveals robust and durable antitumor activity of the preclinical RAS(ON) multiselective inhibitor RMC-7977 against difficult-to-treat subsets of KRASG12C-mutant NSCLC with primary or acquired RASG12C inhibitor resistance and identifies a conserved mucinous transcriptional state that supports RAS inhibitor tolerance.See related commentary by Marasco and Misale, p. 2018

引用

页码：2183 / 2208

页数：26

共 83 条

[1] Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage [J].

Aran, Dvir ;

Looney, Agnieszka P. ;

Liu, Leqian ;

Wu, Esther ;

Fong, Valerie ;

Hsu, Austin ;

Chak, Suzanna ;

Naikawadi, Ram P. ;

Wolters, Paul J. ;

Abate, Adam R. ;

Butte, Atul J. ;

Bhattacharya, Mallar .

NATURE IMMUNOLOGY, 2019, 20 (02) :163-+

[2] Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) [J].

Arbour, K. C. ;

Punekar, S. ;

Garrido-Laguna, I. ;

Hong, D. S. ;

Wolpin, B. ;

Pelster, M. S. ;

Barve, M. ;

Starodub, A. ;

Sommerhalder, D. ;

Chang, S. ;

Zhang, Y. ;

Salman, Z. ;

Wang, X. ;

Gustafson, C. ;

Spira, A. I. .

ANNALS OF ONCOLOGY, 2023, 34 :S458-S458

[3] 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

[4] The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy [J].

Briere, David M. ;

Li, Shuai ;

Calinisan, Andrew ;

Sudhakar, Niranjan ;

Aranda, Ruth ;

Hargis, Lauren ;

Peng, David H. ;

Deng, Jiehui ;

Engstrom, Lars D. ;

Hallin, Jill ;

Gatto, Sole ;

Fernandez-Banet, Julio ;

Pavlicek, Adam ;

Wong, Kwok-Kin ;

Christensen, James G. ;

Olson, Peter .

MOLECULAR CANCER THERAPEUTICS, 2021, 20 (06) :975-985

[5] Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer [J].

Cabanos, Heidie Frisco ;

Hata, Aaron N. .

CANCERS, 2021, 13 (11)

[6] The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity [J].

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 .

NATURE, 2019, 575 (7781) :217-+

[7] MUC1: Structure, Function, and Clinic Application in Epithelial Cancers [J].

Chen, Wenqing ;

Zhang, Zhu ;

Zhang, Shiqing ;

Zhu, Peili ;

Ko, Joshua Ka-Shun ;

Yung, Ken Kin-Lam .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2021, 22 (12)

[8] Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples [J].

Cibulskis, Kristian ;

Lawrence, Michael S. ;

Carter, Scott L. ;

Sivachenko, Andrey ;

Jaffe, David ;

Sougnez, Carrie ;

Gabriel, Stacey ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2013, 31 (03) :213-219

[9] Sotorasib versus docetaxel for previously treated non-small- cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial [J].

de Langen, Adrianus Johannes ;

Johnson, Melissa L. ;

Mazieres, Julien ;

Dingemans, Anne -Marie C. ;

Mountzios, Giannis ;

Pless, Miklos ;

Wolf, Jurgen ;

Schuler, Martin ;

Lena, Herve ;

Skoulidis, Ferdinandos ;

Yoneshima, Yasuto ;

Kim, Sang-We ;

Linardou, Helena ;

Novello, Silvia ;

van der Wekken, Anthonie J. ;

Chen, Yuanbin ;

Peters, Solange ;

Felip, Enriqueta ;

Solomon, Benjamin J. ;

Ramalingam, Suresh S. ;

Dooms, Christophe ;

Lindsay, Colin R. ;

Ferreira, Carlos Gil ;

Blais, Normand ;

Obiozor, Cynthia C. ;

Wang, Yang ;

Mehta, Bhakti ;

Varrieur, Tracy ;

Ngarmchamnanrith, Gataree ;

Stollenwerk, Bjorn ;

Waterhouse, David ;

Paz-Ares, Luis .

LANCET, 2023, 401 (10378) :733-746

[10] SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy [J].

Drilon, Alexander ;

Sharma, Manish R. ;

Johnson, Melissa L. ;

Yap, Timothy A. ;

Gadgeel, Shirish ;

Nepert, Dale ;

Feng, Gang ;

Reddy, Micaela B. ;

Harney, Allison S. ;

Elsayed, Mohamed ;

Cook, Adam W. ;

Wong, Christina E. ;

Hinklin, Ronald J. ;

Jiang, Yutong ;

Brown, Eric N. ;

Neitzel, Nickolas A. ;

Laird, Ellen R. ;

Wu, Wen -, I ;

Singh, Anurag ;

Wei, Ping ;

Ching, Keith A. ;

Gaudino, John J. ;

Lee, Patrice A. ;

Hartley, Dylan P. ;

Rothenberg, S. Michael .

CANCER DISCOVERY, 2023, 13 (08) :1789-1801

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