HER3 Activation Contributes Toward the Emergence of ALK Inhibitor-tolerant Cells in ALK-rearranged Lung Cancer with Mesenchymal Features

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2022 Jan 19

PMID 35042943

Authors

Keiko Tanimura

Tadaaki Yamada

Koutaroh Okada

Kunihiro Nakai

Mano Horinaka

Yuki Katayama

Kenji Morimoto

Yuri Ogura

Takayuki Takeda

Shinsuke Shiotsu

Kosuke Ichikawa

Satoshi Watanabe

Yoshie Morimoto

Masahiro Iwasaku

Yoshiko Kaneko

Junji Uchino

Hirokazu Taniguchi

Kazue Yoneda

Satoaki Matoba

Toshiyuki Sakai

Hisanori Uehara

Seiji Yano

Tetsuro Kusaba

Ryohei Katayama

Koichi Takayama

Affiliations

Soon will be listed here.

Abstract

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.

Citing Articles

Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.

Sampson J, Ju H, Zhang N, Yeoh S, Choi J, Bayliss R Cell Death Dis. 2024; 15(12):912.

PMID: 39695132 PMC: 11655848. DOI: 10.1038/s41419-024-07272-7.

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer.

Fujimura T, Furugaki K, Mizuta H, Muraoka S, Nishio M, Adachi J NPJ Precis Oncol. 2024; 8(1):264.

PMID: 39551860 PMC: 11570601. DOI: 10.1038/s41698-024-00757-w.

Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer.

Furugaki K, Fujimura T, Sakaguchi N, Watanabe Y, Uchibori K, Miyauchi E Mol Oncol. 2024; 19(2):519-539.

PMID: 39369284 PMC: 11793004. DOI: 10.1002/1878-0261.13746.

Gene Fusions-What Promise Remains Behind These Rare Genetic Alterations? A Comprehensive Review of Biology, Diagnostic Approaches, and Clinical Implications.

Kucharczyk T, Nicos M, Kucharczyk M, Kalinka E Cancers (Basel). 2024; 16(15).

PMID: 39123493 PMC: 11311641. DOI: 10.3390/cancers16152766.

Targeting of drug-tolerant persister cells as an approach to counter drug resistance in non-small cell lung cancer.

Izumi M, Costa D, Kobayashi S Lung Cancer. 2024; 194:107885.

PMID: 39002493 PMC: 11305904. DOI: 10.1016/j.lungcan.2024.107885.

References

Miller K, Sauer A, Ortiz A, Fedewa S, Pinheiro P, Tortolero-Luna G . Cancer Statistics for Hispanics/Latinos, 2018. CA Cancer J Clin. 2018; 68(6):425-445. DOI: 10.3322/caac.21494. View

Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A . Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006; 24(28):4539-44. DOI: 10.1200/JCO.2005.04.4859. View

Li T, Kung H, Mack P, Gandara D . Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013; 31(8):1039-49. PMC: 3589700. DOI: 10.1200/JCO.2012.45.3753. View

Recondo G, Facchinetti F, Olaussen K, Besse B, Friboulet L . Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?. Nat Rev Clin Oncol. 2018; 15(11):694-708. DOI: 10.1038/s41571-018-0081-4. View

Soda M, Choi Y, Enomoto M, Takada S, Yamashita Y, Ishikawa S . Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007; 448(7153):561-6. DOI: 10.1038/nature05945. View

Koivunen J, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes A . EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008; 14(13):4275-83. PMC: 3025451. DOI: 10.1158/1078-0432.CCR-08-0168. View

Shaw A, Kim D, Nakagawa K, Seto T, Crino L, Ahn M . Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013; 368(25):2385-94. DOI: 10.1056/NEJMoa1214886. View

Hida T, Nokihara H, Kondo M, Kim Y, Azuma K, Seto T . Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017; 390(10089):29-39. DOI: 10.1016/S0140-6736(17)30565-2. View

Peters S, Camidge D, Shaw A, Gadgeel S, Ahn J, Kim D . Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 377(9):829-838. DOI: 10.1056/NEJMoa1704795. View

10.

Camidge D, Kim H, Ahn M, Yang J, Han J, Lee J . Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379(21):2027-2039. DOI: 10.1056/NEJMoa1810171. View

11.

Solomon B, Besse B, Bauer T, Felip E, Soo R, Camidge D . Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018; 19(12):1654-1667. DOI: 10.1016/S1470-2045(18)30649-1. View

12.

Katayama R . Drug resistance in anaplastic lymphoma kinase-rearranged lung cancer. Cancer Sci. 2018; 109(3):572-580. PMC: 5834792. DOI: 10.1111/cas.13504. View

13.

Fukuda K, Takeuchi S, Arai S, Katayama R, Nanjo S, Tanimoto A . Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of Mutation Status. Cancer Res. 2019; 79(7):1658-1670. DOI: 10.1158/0008-5472.CAN-18-2052. View

14.

Kim D, Tiseo M, Ahn M, Reckamp K, Hansen K, Kim S . Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol. 2017; 35(22):2490-2498. DOI: 10.1200/JCO.2016.71.5904. View

15.

Shaw A, Solomon B, Besse B, Bauer T, Lin C, Soo R . Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2019; 37(16):1370-1379. PMC: 6544460. DOI: 10.1200/JCO.18.02236. View

16.

Sharma S, Lee D, Li B, Quinlan M, Takahashi F, Maheswaran S . A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010; 141(1):69-80. PMC: 2851638. DOI: 10.1016/j.cell.2010.02.027. View

17.

Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A . AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat Commun. 2019; 10(1):259. PMC: 6335418. DOI: 10.1038/s41467-018-08074-0. View

18.

Arasada R, Shilo K, Yamada T, Zhang J, Yano S, Ghanem R . Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC. Nat Commun. 2018; 9(1):3198. PMC: 6090531. DOI: 10.1038/s41467-018-05626-2. View

19.

Suda K, Murakami I, Sakai K, Tomizawa K, Mizuuchi H, Sato K . Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer. Lung Cancer. 2015; 91:36-40. DOI: 10.1016/j.lungcan.2015.11.016. View

20.

Jamal-Hanjani M, Wilson G, McGranahan N, Birkbak N, Watkins T, Veeriah S . Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 376(22):2109-2121. DOI: 10.1056/NEJMoa1616288. View