Synergism of FAK and ROS1 Inhibitors in the Treatment of -deficient Cancers Mediated by FAK-YAP Signaling

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2023 Jun 16

PMID 37324948

Authors

Jiaming Gao

Yunying Yao

Chenxuan Liu

Xi Xie

Donghe Li

Ping Liu

Zaiqi Wang

Baoyuan Zhang

Ruibao Ren

Affiliations

Soon will be listed here.

Abstract

deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in -deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of the FAK activity accompanies the emergence of resistance to ROS1 inhibitor therapy in gastric and breast -deficient cancers. FAK inhibition, either by FAK inhibitors or by knocking down its expression, resulted in higher cytotoxicity potency of the ROS1 inhibitor in -deficient cancer cell lines. Co-treatment of mice with the FAK inhibitor and ROS1 inhibitors also showed synergistic effects against -deficient cancers. Mechanistically, ROS1 inhibitors induce the FAK-YAP-TRX signaling, decreasing oxidative stress-related DNA damage and consequently reducing their anti-cancer effects. The FAK inhibitor suppresses the aberrant FAK-YAP-TRX signaling, reinforcing ROS1 inhibitor's cytotoxicity towards cancer cells. These findings support the use of FAK and ROS1 inhibitors as a combination therapeutic strategy in -deficient triple negative breast cancer and diffuse gastric cancer patients.

Citing Articles

Exploring the Role of Thioredoxin system in Cancer Immunotherapy.

Sun L, Yu A, Yang Y, Wang Z, Wang W, Luo L J Cancer. 2025; 16(1):66-80.

PMID: 39744566 PMC: 11660121. DOI: 10.7150/jca.98306.

and its flavonoids in the treatment of digestive system tumors.

Zhao K, Zhang J, Zhou L, Sun Z Front Pharmacol. 2024; 15:1483785.

PMID: 39654621 PMC: 11625591. DOI: 10.3389/fphar.2024.1483785.

Impact of Molecular Profiling on Therapy Management in Breast Cancer.

Ultimescu F, Hudita A, Popa D, Olinca M, Muresean H, Ceausu M J Clin Med. 2024; 13(17).

PMID: 39274207 PMC: 11396537. DOI: 10.3390/jcm13174995.

Recycling machinery of integrin coupled with focal adhesion turnover via RAB11-UNC13D-FAK axis for migration of pancreatic cancer cells.

Duong V, Ha M, Kim J, Kim J, Park S, Reshma K J Transl Med. 2024; 22(1):800.

PMID: 39210440 PMC: 11360766. DOI: 10.1186/s12967-024-05630-9.

Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance.

Eshaq A, Flanagan T, Hassan S, Al Asheikh S, Al-Amoudi W, Santourlidis S Cancers (Basel). 2024; 16(15).

PMID: 39123481 PMC: 11311543. DOI: 10.3390/cancers16152754.

References

Desmedt C, Zoppoli G, Gundem G, Pruneri G, Larsimont D, Fornili M . Genomic Characterization of Primary Invasive Lobular Breast Cancer. J Clin Oncol. 2016; 34(16):1872-81. DOI: 10.1200/JCO.2015.64.0334. View

Wang Y, Tian P, Xia L, Li L, Han R, Zhu M . The clinical efficacy of combinatorial therapy of EGFR-TKI and crizotinib in overcoming MET amplification-mediated resistance from prior EGFR-TKI therapy. Lung Cancer. 2020; 146:165-173. DOI: 10.1016/j.lungcan.2020.06.003. View

Shao D, Zhai P, Del Re D, Sciarretta S, Yabuta N, Nojima H . A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat Commun. 2014; 5:3315. PMC: 3962829. DOI: 10.1038/ncomms4315. View

Pietila E, Gonzalez-Molina J, Moyano-Galceran L, Jamalzadeh S, Zhang K, Lehtinen L . Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance. Nat Commun. 2021; 12(1):3904. PMC: 8222388. DOI: 10.1038/s41467-021-24009-8. View

Paradis J, Acosta M, Saddawi-Konefka R, Kishore A, Gomes F, Arang N . Synthetic Lethal Screens Reveal Cotargeting FAK and MEK as a Multimodal Precision Therapy for -Driven Uveal Melanoma. Clin Cancer Res. 2021; 27(11):3190-3200. PMC: 8895627. DOI: 10.1158/1078-0432.CCR-20-3363. View

Le Large T, Bijlsma M, El Hassouni B, Mantini G, Lagerweij T, Henneman A . Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res. 2021; 40(1):91. PMC: 7941981. DOI: 10.1186/s13046-021-01892-z. View

Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N . Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007; 297(21):2360-72. DOI: 10.1001/jama.297.21.2360. View

Jiang H, Liu X, Knolhoff B, Hegde S, Lee K, Jiang H . Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion. Gut. 2019; 69(1):122-132. PMC: 7167297. DOI: 10.1136/gutjnl-2018-317424. View

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

10.

Zhang J, Li X, Han X, Liu R, Fang J . Targeting the Thioredoxin System for Cancer Therapy. Trends Pharmacol Sci. 2017; 38(9):794-808. DOI: 10.1016/j.tips.2017.06.001. View

11.

Song X, Xu H, Wang P, Wang J, Affo S, Wang H . Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation. J Hepatol. 2021; 75(4):888-899. PMC: 8453055. DOI: 10.1016/j.jhep.2021.05.018. View

12.

Shaw A, Ou S, Bang Y, Camidge D, Solomon B, Salgia R . Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014; 371(21):1963-71. PMC: 4264527. DOI: 10.1056/NEJMoa1406766. View

13.

Dey A, Varelas X, Guan K . Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat Rev Drug Discov. 2020; 19(7):480-494. PMC: 7880238. DOI: 10.1038/s41573-020-0070-z. View

14.

Xu Q, Zhang J, Telfer B, Zhang H, Ali N, Chen F . The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion. Oncogene. 2021; 40(23):3929-3941. PMC: 8195737. DOI: 10.1038/s41388-021-01798-2. View

15.

Dawson J, Serrels A, Stupack D, Schlaepfer D, Frame M . Targeting FAK in anticancer combination therapies. Nat Rev Cancer. 2021; 21(5):313-324. PMC: 8276817. DOI: 10.1038/s41568-021-00340-6. View

16.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

17.

Zhang B, Zhang Y, Zhang J, Liu P, Jiao B, Wang Z . Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK-YAP Signaling. Adv Sci (Weinh). 2021; 8(16):e2100250. PMC: 8373085. DOI: 10.1002/advs.202100250. View

18.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

19.

Lin J, Choudhury N, Yoda S, Zhu V, Johnson T, Sakhtemani R . Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in Fusion-Positive Lung Cancer. Clin Cancer Res. 2021; 27(10):2899-2909. PMC: 8127383. DOI: 10.1158/1078-0432.CCR-21-0032. View

20.

Bajrami I, Marlow R, van de Ven M, Brough R, Pemberton H, Frankum J . E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer. Cancer Discov. 2018; 8(4):498-515. PMC: 6296442. DOI: 10.1158/2159-8290.CD-17-0603. View