Overcoming Therapy Resistance in Colorectal Cancer: Targeting the Rac1 Signaling Pathway as a Potential Therapeutic Approach.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Colorectal Neoplasms*/drug therapy ; Colorectal Neoplasms*/genetics ; Colorectal Neoplasms*/pathology ; Colorectal Neoplasms*/metabolism ; rac1 GTP-Binding Protein*/metabolism ; rac1 GTP-Binding Protein*/genetics ; rac1 GTP-Binding Protein*/antagonists & inhibitors ; Drug Resistance, Neoplasm*/drug effects ; Drug Resistance, Neoplasm*/genetics ; Signal Transduction*/drug effects ; Fluorouracil*/pharmacology ; Fluorouracil*/therapeutic use; Humans ; Animals ; Cell Line, Tumor ; Mice ; Gene Expression Regulation, Neoplastic/drug effects ; Xenograft Model Antitumor Assays ; Mice, Nude ; Cell Proliferation/drug effects

Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide and is responsible for numerous deaths. 5-fluorouracil (5-FU) is an effective chemotherapy drug commonly used in the treatment of CRC, either as monotherapy or in combination with other drugs. However, half of CRC cases are resistant to 5-FU-based therapies. To contribute to the understanding of the mechanisms underlying CRC resistance or recurrence after 5-FU-based therapies, we performed a comprehensive study integrating in silico, in vitro, and in vivo approaches. We identified differentially expressed genes and enrichment of pathways associated with recurrence after 5-FU-based therapies. Using these bioinformatics data as a starting point, we selected a group of drugs that restored 5-FU sensitivity to 5-FU resistant cells. Interestingly, treatment with the novel Rac1 inhibitor, 1A-116, reversed morphological changes associated with 5-FU resistance.. Moreover, our in vivo studies have shown that 1A-116 affected tumor growth and the development of metastasis. All our data allowed us to postulate that targeting Rac1 represents a promising avenue for the development of new treatments for patients with CRC resistant to 5-FU-based therapies.

Cancer Sci. 2020 Sep;111(9):3142-3154. (PMID: 32536012)
PLoS Comput Biol. 2014 Jul 24;10(7):e1003731. (PMID: 25058159)
Crit Rev Oncol Hematol. 2018 Apr;124:29-36. (PMID: 29548483)
Cancer Res. 2014 Jun 1;74(11):2913-21. (PMID: 24840647)
BMC Bioinformatics. 2011 Mar 17;12:77. (PMID: 21414208)
Eur J Pharmacol. 2022 Oct 15;933:175253. (PMID: 36067803)
Meta Gene. 2016 May 09;9:110-9. (PMID: 27331015)
Genes Dev. 1997 Sep 15;11(18):2295-322. (PMID: 9308960)
Bioinformatics. 2012 Mar 15;28(6):882-3. (PMID: 22257669)
Cancers (Basel). 2022 Sep 30;14(19):. (PMID: 36230732)
Int J Clin Oncol. 2018 Jun;23(3):490-496. (PMID: 29464396)
J Pathol. 2005 Jan;205(2):275-92. (PMID: 15641020)
Autophagy. 2016 Dec;12(12):2498-2499. (PMID: 27657889)
Mol Cell Biol. 1997 Mar;17(3):1324-35. (PMID: 9032259)
Nat Med. 2015 Nov;21(11):1350-6. (PMID: 26457759)
CA Cancer J Clin. 2024 May-Jun;74(3):229-263. (PMID: 38572751)
BMC Syst Biol. 2014;8 Suppl 4:S11. (PMID: 25521941)
Comput Biol Med. 2015 Dec 1;67:136-45. (PMID: 26520484)
Cancer Cell. 2019 Jul 8;36(1):68-83.e9. (PMID: 31257073)
Toxicol Res. 2015 Jun;31(2):151-6. (PMID: 26191381)
Lancet. 2000 Mar 25;355(9209):1041-7. (PMID: 10744089)
J Clin Oncol. 2004 Jan 1;22(1):23-30. (PMID: 14665611)
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D562-6. (PMID: 15608262)
Biomed Pharmacother. 2021 May;137:111285. (PMID: 33485118)
Eur J Cancer. 1996;32A Suppl 3:S24-31. (PMID: 8943662)
J Cell Mol Med. 2020 May;24(9):5387-5401. (PMID: 32237037)
Ann Oncol. 2004 Jul;15(7):1025-32. (PMID: 15205195)
Oncotarget. 2016 Apr 19;7(16):22077-91. (PMID: 26956045)
Cancer Res. 2008 Feb 1;68(3):826-33. (PMID: 18245484)
Biostatistics. 2003 Apr;4(2):249-64. (PMID: 12925520)
Bioinformatics. 2011 Jun 15;27(12):1739-40. (PMID: 21546393)
Nature. 2019 Nov;575(7782):299-309. (PMID: 31723286)
Oncol Lett. 2019 Aug;18(2):2091-2101. (PMID: 31423282)
PLoS One. 2013 Apr 30;8(4):e63177. (PMID: 23646193)
FEBS Lett. 2008 Jun 18;582(14):2093-101. (PMID: 18460342)
Biochim Biophys Acta. 2004 Dec 17;1705(2):121-32. (PMID: 15588766)
Gastrointest Endosc Clin N Am. 2022 Apr;32(2):195-213. (PMID: 35361331)
Clin Exp Pharmacol Physiol. 1998 Nov;25(11):887-95. (PMID: 9807659)
Front Cell Dev Biol. 2021 Nov 30;9:786728. (PMID: 34917620)
Commun Biol. 2022 Oct 7;5(1):1068. (PMID: 36207615)
Cell. 2017 Nov 30;171(6):1437-1452.e17. (PMID: 29195078)
Clin Colorectal Cancer. 2015 Mar;14(1):1-10. (PMID: 25579803)
Prog Biophys Mol Biol. 2019 Jan;141:15-24. (PMID: 30031023)
Physiol Rev. 2013 Jan;93(1):269-309. (PMID: 23303910)
Mol Biol Rep. 2019 Dec;46(6):5831-5839. (PMID: 31741260)
Genome Res. 2003 Nov;13(11):2498-504. (PMID: 14597658)
Oncol Res. 2018 Sep 14;26(8):1191-1200. (PMID: 29386087)
Sci Rep. 2021 Apr 14;11(1):8091. (PMID: 33854147)
Bioinformatics. 2005 Oct 15;21(20):3940-1. (PMID: 16096348)
Front Immunol. 2022 Jun 17;13:887048. (PMID: 35784334)
Cell Mol Life Sci. 2009 Feb;66(3):370-4. (PMID: 19151919)
Science. 1998 Jan 23;279(5350):509-14. (PMID: 9438836)
Oncotarget. 2015 Dec 8;6(39):41706-21. (PMID: 26527315)
Medicine (Baltimore). 2020 Apr;99(17):e19931. (PMID: 32332673)
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
Small GTPases. 2016 Oct;7(4):207-221. (PMID: 27628050)
Cancer Res. 2007 May 1;67(9):4425-33. (PMID: 17483357)
Bioinformatics. 2007 Jul 15;23(14):1846-7. (PMID: 17496320)
Nat Med. 2013 May;19(5):619-25. (PMID: 23584089)
Cancer Res. 2003 Aug 1;63(15):4602-6. (PMID: 12907638)
Nat Rev Cancer. 2003 May;3(5):330-8. (PMID: 12724731)
Front Genet. 2020 Apr 03;11:247. (PMID: 32346383)
Cancer Res. 2013 Mar 15;73(6):1958-68. (PMID: 23328581)
Cell Rep. 2016 Mar 8;14(9):2193-2208. (PMID: 26923603)
Mol Ther Oncolytics. 2021 Jul 10;23:14-25. (PMID: 34589581)
Bioinformatics. 2006 Nov 15;22(22):2825-7. (PMID: 16982708)
Science. 2019 Dec 20;366(6472):1473-1480. (PMID: 31699882)
Biochem Pharmacol. 2022 Sep;203:115180. (PMID: 35853497)
Cancers (Basel). 2022 Mar 29;14(7):. (PMID: 35406504)
Biomedicines. 2022 Aug 04;10(8):. (PMID: 36009428)
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21. (PMID: 11309499)
Cancer Res. 2007 Mar 1;67(5):2226-38. (PMID: 17332353)
J Clin Oncol. 2000 Jan;18(1):136-47. (PMID: 10623704)
Front Oncol. 2021 Apr 12;11:604315. (PMID: 33912443)
Cancer Res. 2016 Aug 1;76(15):4457-69. (PMID: 27302166)
Nat Commun. 2020 Oct 21;11(1):5321. (PMID: 33087710)
Nucleic Acids Res. 2017 Jan 4;45(D1):D362-D368. (PMID: 27924014)
Oncotarget. 2017 Oct 4;8(58):98509-98523. (PMID: 29228706)
Br J Cancer. 2021 Jan;124(2):375-382. (PMID: 32994466)
Front Oncol. 2021 May 17;11:674426. (PMID: 34079763)
Clin Exp Metastasis. 2018 Apr;35(4):309-318. (PMID: 29799080)
Anticancer Agents Med Chem. 2014;14(6):840-51. (PMID: 24066799)
EMBO J. 2011 Aug 26;30(19):3913-27. (PMID: 21873980)
Mol Biosyst. 2016 Feb;12(2):477-9. (PMID: 26661513)
Transl Oncol. 2021 Oct;14(10):101174. (PMID: 34243011)
Cancers (Basel). 2020 Jun 11;12(6):. (PMID: 32545340)
J Biol Chem. 1999 Mar 26;274(13):8506-15. (PMID: 10085083)
Mol Cancer Ther. 2009 Jun;8(6):1557-69. (PMID: 19509242)
Mol Cancer Res. 2006 Aug;4(8):521-8. (PMID: 16877703)
Cancer Res. 2008 Sep 15;68(18):7323-31. (PMID: 18794119)
Cold Spring Harb Symp Quant Biol. 1998;63:643-51. (PMID: 10384329)

Asistencia Financiera III, 2015 Instituto Nacional del Cáncer; PICT2018-0900 and PICT2019-0801 Agencia Nacional de Promoción Científica y Tecnológica; PEICID-2021-106 Agencia Santafesina de Ciencia, Tecnología e Innovación; Investigación en Ciencias Biomédicas Fundación Florencio Fiorini

Keywords: Rac1; colorectal cancer; repositioning; resistance; small GTPases

EC 3.6.5.2 (rac1 GTP-Binding Protein)
U3P01618RT (Fluorouracil)
0 (RAC1 protein, human)

Date Created: 20241108 Date Completed: 20241108 Latest Revision: 20241116

20241116

PMC11545287

10.3390/cells13211776

39513883