2. Academic Validation
  3. Targeting KRAS mutant cancers: from druggable therapy to drug resistance

Targeting KRAS mutant cancers: from druggable therapy to drug resistance

  • Mol Cancer. 2022 Aug 4;21(1):159. doi: 10.1186/s12943-022-01629-2.
Chunxiao Zhu # 1 2,  Xiaoqing Guan # 1 3,  Xinuo Zhang # 1 4,  Xin Luan 5,  Zhengbo Song 1,  Xiangdong Cheng 6 7,  Weidong Zhang 8 9,  Jiang-Jiang Qin 10 11 12
Affiliations

Affiliations

  • 1 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.
  • 2 School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China.
  • 3 Key Laboratory of Prevention, Diagnosis, and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China.
  • 4 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310032, China.
  • 5 Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 6 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China. [email protected].
  • 7 Key Laboratory of Prevention, Diagnosis, and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China. [email protected].
  • 8 Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].
  • 9 School of Pharmacy, Second Military Medical University, Shanghai, 200433, China. [email protected].
  • 10 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China. [email protected].
  • 11 School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China. [email protected].
  • 12 Key Laboratory of Prevention, Diagnosis, and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China. [email protected].
  • # Contributed equally.
PMID: 35922812 DOI: 10.1186/s12943-022-01629-2
Abstract

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

Keywords

Combination therapy; Druggable; KRAS mutations; Resistance.

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