Strategies to tackle RAS -mutated metastatic colorectal cancer

ESMO Open

article

G. Patelli¹  F. Tosi¹  A. Amatu¹  G. Mauri¹  A. Curaba¹  D.A. Patanè¹  A. Pani²  F. Scaglione²  S. Siena¹  A. Sartore-Bianchi¹ 

[1] Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda;Department of Oncology and Hemato-Oncology, Università degli Studi di Milano;Clinical Pharmacology Unit, Grande Ospedale Metropolitano Niguarda

关键词: RAS;    KRAS;    sotorasib;    adagrasib;    colorectal cancer;   

DOI  :  10.1016/j.esmoop.2021.100156

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as ‘undruggable'. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as ‘undruggable' and future avenues are now opening for translation in the clinic in mCRC.

【 授权许可】

CC BY|CC BY-NC-ND