Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer

被引：26

作者：

Mohanty, Atish ^{[1
]}

Nam, Arin ^{[1
]}

Srivastava, Saumya ^{[1
]}

Jones, Jeff ^{[2
]}

Lomenick, Brett ^{[2
]}

Singhal, Sharad S. ^{[1
]}

Guo, Linlin ^{[1
]}

Cho, Hyejin ^{[3
]}

Li, Aimin ^{[4
]}

Behal, Amita ^{[1
]}

Mirzapoiazova, Tamara ^{[1
]}

Massarelli, Erminia ^{[1
]}

Koczywas, Marianna ^{[1
]}

Arvanitis, Leonidas D. ^{[4
]}

Walser, Tonya ^{[1
]}

Villaflor, Victoria ^{[1
]}

Hamilton, Stanley ^{[4
]}

Mambetsariev, Isa ^{[1
]}

Sattler, Martin ^{[5
]}

Nasser, Mohd W. ^{[6
]}

Jain, Maneesh ^{[6
]}

Batra, Surinder K. ^{[6
]}

Soldi, Raffaella ^{[7
]}

Sharma, Sunil ^{[7
]}

Fakih, Marwan ^{[1
]}

Mohanty, Saswat Kumar ^{[8
]}

Mainan, Avijit ^{[8
]}

Wu, Xiwei ^{[3
]}

Chen, Yihong ^{[9
]}

He, Yanan ^{[9
]}

Chou, Tsui-Fen ^{[2
]}

Roy, Susmita ^{[8
]}

Orban, John ^{[9
,10
]}

Kulkarni, Prakash ^{[1
]}

Salgia, Ravi ^{[1
]}

机构：

[1] City Hope Natl Med Ctr, Dept Med Oncol & Expt Therapeut, Duarte, CA 91010 USA

[2] CALTECH, Proteome Explorat Lab, Pasadena, CA 91125 USA

[3] City Hope Natl Med Ctr, Beckman Res Inst, Integrat Genom Core, Monrovia, CA 91016 USA

[4] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[6] Univ Nebraska Med Ctr, Biochem & Mol Biol, Omaha, NE 68198 USA

[7] Translat Genom Res Inst TGen City Hope, Appl Canc Res & Drug Discovery Div, Phoenix, AZ 85004 USA

[8] Indian Inst Sci Educ & Res Kolkata, Dept Chem Sci, Mohanpur 741246, W Bengal, India

[9] Univ Maryland, Inst Biosci & Biotechnol Res, WM Keck Lab Struct Biol, Rockville, MD 20850 USA

[10] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA

来源：

SCIENCE ADVANCES | 2023年 / 9卷 / 41期

关键词：

NONGENETIC RESISTANCE; MUTATION; RAS; DISCOVERY; BEHAVIOR; SYNERGY;

D O I：

10.1126/sciadv.ade3816

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin beta 4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/beta-catenin signaling pathway. Thus, silencing both ITGB4 and beta-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and beta-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.

引用

页数：20

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