Sensitivities and Dependencies of BRAF Mutant Colorectal Cancer Cell Lines with or without PIK3CA Mutations for Discovery of Vulnerabilities with Therapeutic Potential

被引:3
|
作者
Voutsadakis, Ioannis A. [1 ,2 ]
机构
[1] Sault Area Hosp, Algoma Dist Canc Program, 750 Great Northern Rd, Sault Ste Marie, ON P6B 0A8, Canada
[2] Northern Ontario Sch Med, Div Clin Sci, Sect Internal Med, Sudbury, ON P3E 2C6, Canada
来源
MEDICINA-LITHUANIA | 2022年 / 58卷 / 10期
关键词
colon cancer; cell line models; dependencies; targeted therapy; signal transduction; GENOMIC LANDSCAPE; EXPRESSION; SPECIFICITY; ENCORAFENIB; ACTIVATION; CETUXIMAB; PATHWAY; ARK5;
D O I
10.3390/medicina58101498
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Colorectal cancer represents a common malignancy and remains incurable in the metastatic stage. Identification of molecular alterations that are present in colorectal cancer has led to the introduction of targeted therapies that improve outcomes. BRAF and PIK3CA mutations are observed in a subset of colorectal cancers. Colorectal cancers bearing BRAF mutations may be treated with specific BRAF inhibitors. These drugs benefit patients with BRAF mutant colorectal cancers but responses are rather brief, and progression is the rule. In contrast, no PI3K inhibitors have proven successful yet in the disease. Thus, new treatments to supplement the currently available drugs would be welcome to further improve survival. Methods: Profiled colorectal cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were examined for BRAF and PIK3CA mutations and were interrogated for molecular characteristics and concomitant alterations that mirror clinical sample alterations. The Genomics of Drug Sensitivity in Cancer (GDSC) project was used for determination of drug sensitivities of BRAF mutated colorectal cell lines with or without concomitant PIK3CA mutations. The Cancer Dependency Map project served as the basis for identification of molecular dependencies and vulnerabilities in these cell lines. Results: CCLE includes 84 colorectal cancer cell lines, which recapitulate the molecular landscape of colorectal cancer. Of these, 23 and 24 cell lines possess BRAF and PIK3CA mutations, respectively. Seven BRAF mutant cell lines have V600E mutations and 14 PIK3CA mutant cell lines have hotspot helical or kinase domain mutations. V600E BRAF mutant cell lines with or without hotspot PIK3CA mutations are heterogeneous in their MSI status and mimic colorectal cancer tissues in other prevalent abnormalities including APC and TP53 mutations. Essential genes for survival include CTNNB1, WRN, and pyrimidine metabolism enzyme CAD. Besides BRAF mutations, BRAF inhibitor sensitivity in colorectal cancer cell lines is conferred by SACS mutations and PRKN locus loss. Conclusions: Colorectal cancer cell lines bearing the frequent BRAF and PIK3CA mutations present many alterations of the parental cancer tissue. Described vulnerabilities represent leads for therapeutic exploration in colorectal cancers with the corresponding alterations.
引用
收藏
页数:15
相关论文
共 50 条
  • [11] Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer
    Hao, Yujun
    Samuels, Yardena
    Li, Qingling
    Krokowski, Dawid
    Guan, Bo-Jhih
    Wang, Chao
    Jin, Zhicheng
    Dong, Bohan
    Cao, Bo
    Feng, Xiujing
    Xiang, Min
    Xu, Claire
    Fink, Stephen
    Meropol, Neal J.
    Xu, Yan
    Conlon, Ronald A.
    Markowitz, Sanford
    Kinzler, Kenneth W.
    Velculescu, Victor E.
    Brunengraber, Henri
    Willis, Joseph E.
    LaFramboise, Thomas
    Hatzoglou, Maria
    Zhang, Guo-Fang
    Vogelstein, Bert
    Wang, Zhenghe
    NATURE COMMUNICATIONS, 2016, 7
  • [12] Prognostic and Predictive Value of PIK3CA Mutations in Metastatic Colorectal Cancer
    Tan, Elaine S.
    Fan, Wenyi
    Knepper, Todd C.
    Schell, Michael J.
    Sahin, Ibrahim H.
    Fleming, Jason B.
    Xie, Hao
    TARGETED ONCOLOGY, 2022, 17 (04) : 483 - 492
  • [13] PIK3CA mutations in KRAS and BRAF wild type colorectal cancer patients. A study of Spanish population
    Marta Herreros-Villanueva
    Noemí Gomez-Manero
    Pilar Muñiz
    Carlos García-Girón
    Maria Jesús Coma del Corral
    Molecular Biology Reports, 2011, 38 : 1347 - 1351
  • [14] Characteristics and prevalence of KRAS, BRAF, and PIK3CA mutations in colorectal cancer by high-resolution melting analysis in Taiwanese population
    Hsieh, Li-Ling
    Er, Tze-Kiong
    Chen, Chih-Chieh
    Hsieh, Jan-Sing
    Chang, Jan-Gowth
    Liu, Ta-Chih
    CLINICA CHIMICA ACTA, 2012, 413 (19-20) : 1605 - 1611
  • [15] PIK3CA Mutations in Resected Small Cell Lung Cancer
    Han, Na
    Cheng, Qiao-Yuan
    Chen, Bo
    Cai, Ju-Fen
    Wang, Xiao-Jia
    Lou, Cai-Jin
    Qin, Jing
    Ye, Wei-Wu
    Lei, Lei
    Lu, Hong-Yang
    ADVANCES IN CLINICAL AND EXPERIMENTAL MEDICINE, 2016, 25 (03): : 397 - 402
  • [16] PI3K expression and PIK3CA mutations are related to colorectal cancer metastases
    Zhu, Yu-Fen
    Yu, Bao-Hua
    Li, Da-Li
    Ke, Hong-Lin
    Guo, Xian-Zhi
    Xiao, Xiu-Ying
    WORLD JOURNAL OF GASTROENTEROLOGY, 2012, 18 (28) : 3745 - 3751
  • [17] High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer
    Simi, Lisa
    Pratesi, Nicola
    Vignoli, Marina
    Sestini, Roberta
    Cianchi, Fabio
    Valanzano, Rosa
    Nobili, Stefania
    Mini, Enrico
    Pazzagli, Mario
    Orlando, Claudio
    AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 2008, 130 (02) : 247 - 253
  • [18] Survey of KRAS, BRAF and PIK3CA mutational status in 209 consecutive Italian colorectal cancer patients
    Bozzao, Cristina
    Varvara, Dora
    Piglionica, Marilidia
    Bagnulo, Rosanna
    Forte, Giovanna
    Patruno, Margherita
    Russo, Silvana
    Piscitelli, Domenico
    Stella, Alessandro
    Resta, Nicoletta
    INTERNATIONAL JOURNAL OF BIOLOGICAL MARKERS, 2012, 27 (04) : E366 - E374
  • [19] Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases
    Mao, Chen
    Wu, Xin-Yin
    Yang, Zu-Yao
    Threapleton, Diane Erin
    Yuan, Jin-Qiu
    Yu, Yuan-Yuan
    Tang, Jin-Ling
    SCIENTIFIC REPORTS, 2015, 5 : 8065
  • [20] KRAS mutated colorectal cancers with or without PIK3CA mutations: Clinical and molecular profiles inform current and future therapeutics
    Voutsadakis, Ioannis A.
    CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2023, 186