Top

Published in:

Open Access 01-12-2021 | Gastric Cancer | Research

A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer

Authors: Gang Ning, Qihui Zhu, Wonyoung Kang, Hamin Lee, Leigh Maher, Yun-Suhk Suh, Michael Michaud, Mayerlin Silva, Jee Young Kwon, Chengsheng Zhang, Charles Lee

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 13–23% of all GC cases and patients with HER2 overexpression exhibit a poor prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is an effective agent to treat HER2-amplified breast cancer but it failed in gastric cancer (GC) clinical trials. However, the molecular mechanism of lapatinib resistance in HER2-amplified GC is not well studied.

Methods

We employed an unbiased, genome-scale screening with pooled CRISPR library on HER2-amplified GC cell lines to identify genes that are associated with resistance to lapatinib. To validate the candidate genes, we applied in vitro and in vivo pharmacological tests to confirm the function of the target genes.

Results

We found that loss of function of CSK or PTEN conferred lapatinib resistance in HER2-amplified GC cell lines NCI-N87 and OE19, respectively. Moreover, PI3K and MAPK signaling was significantly increased in CSK or PTEN null cells. Furthermore, in vitro and in vivo pharmacological study has shown that lapatinib resistance by the loss of function of CSK or PTEN, could be overcome by lapatinib combined with the PI3K inhibitor copanlisib and MEK inhibitor trametinib.

Conclusions

Our study suggests that loss-of-function mutations of CSK and PTEN cause lapatinib resistance by re-activating MAPK and PI3K pathways, and further proved these two pathways are druggable targets. Inhibiting the two pathways synergistically are effective to overcome lapatinib resistance in HER2-amplified GC. This study provides insights for understanding the resistant mechanism of HER2 targeted therapy and novel strategies that may ultimately overcome resistance or limited efficacy of lapatinib treatment for subset of HER2 amplified GC.

Available only for authorised users

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. https://doi.org/10.3322/caac.20107.CrossRefPubMed

Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10:239–48. https://doi.org/10.2147/CMAR.S149619.CrossRefPubMedPubMedCentral

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. https://doi.org/10.3322/caac.21551.CrossRefPubMed

Van Cutsem E, Bang Y-J, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18(3):476–84. https://doi.org/10.1007/s10120-014-0402-y.CrossRefPubMed

Ayed-Guerfali D, Abid N, Khabir A, Mnif H, Khanfir A, Boujelbène S, et al. Expression of human epidermal growth factor receptor 2 and p53 in gastric cancer patients: clinical and prognosis relevance. Clin Cancer Investig J. 2016;5(5):424. https://doi.org/10.4103/2278-0513.197866.CrossRef

Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523–9. https://doi.org/10.1093/annonc/mdn169.CrossRefPubMed

Wong H, Yau T. Targeted therapy in the management of advanced gastric cancer: are we making progress in the era of personalized medicine? Oncologist. 2012;17(3):346–58. https://doi.org/10.1634/theoncologist.2011-0311.CrossRefPubMedPubMedCentral

Amir E, Ocaña A, Seruga B, Freedman O, Clemons M. Lapatinib and HER2 status: results of a meta-analysis of randomized phase III trials in metastatic breast cancer. Cancer Treat Rev. 2010;36(5):410–5. https://doi.org/10.1016/j.ctrv.2009.12.012.CrossRefPubMed

Bang Y-J, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97. https://doi.org/10.1016/S0140-6736(10)61121-X.CrossRefPubMed

10.

Hecht JR, Bang Y-J, Qin SK, Chung HC, Xu JM, Park JO, et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2–positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC—A randomized phase III trial. J Clin Oncol. 2016;34(5):443–51. https://doi.org/10.1200/JCO.2015.62.6598.CrossRefPubMed

11.

Janjigian YY. Lapatinib in gastric cancer: what is the LOGiCal next step? J Clin Oncol. 2016;34(5):401–3. https://doi.org/10.1200/JCO.2015.64.2892.CrossRefPubMed

12.

Chen CT, Kim H, Liska D, Gao S, Christensen JG, Weiser MR. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther. 2012;11(3):660–9. https://doi.org/10.1158/1535-7163.MCT-11-0754.CrossRefPubMedPubMedCentral

13.

Kim J, Fox C, Peng S, Pusung M, Pectasides E, Matthee E, et al. Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma. J Clin Invest. 2014;124(12):5145–58. https://doi.org/10.1172/JCI75200.CrossRefPubMedPubMedCentral

14.

Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelsen TS, et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science. 2014;343(6166):84–7. https://doi.org/10.1126/science.1247005.CrossRefPubMed

15.

Koike-Yusa H, Li Y, Tan E-P, Velasco-Herrera MDC, Yusa K. Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library. Nat Biotechnol. 2014;32(3):267–73. https://doi.org/10.1038/nbt.2800.CrossRefPubMed

16.

Evers B, Jastrzebski K, Heijmans JPM, Grernrum W, Beijersbergen RL, Bernards R. CRISPR knockout screening outperforms shRNA and CRISPRi in identifying essential genes. Nat Biotechnol. 2016;34(6):631–3. https://doi.org/10.1038/nbt.3536.CrossRefPubMed

17.

Joung J, Konermann S, Gootenberg JS, Abudayyeh OO, Platt RJ, Brigham MD, et al. Protocol: genome-scale CRISPR-Cas9 knockout and transcriptional activation screening. 2017. Nat Protoc. 2017;12(4):828–63. https://doi.org/10.1038/nprot.2017.016.CrossRefPubMedPubMedCentral

18.

Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10(3):R25. https://doi.org/10.1186/gb-2009-10-3-r25.CrossRefPubMedPubMedCentral

19.

Li W, Xu H, Xiao T, Cong L, Love MI, Zhang F, et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014;15(12):554. https://doi.org/10.1186/s13059-014-0554-4.CrossRefPubMedPubMedCentral

20.

Li W, Köster J, Xu H, Chen CH, Xiao T, Liu JS, et al. Quality control, modeling, and visualization of CRISPR screens with MAGeCK-VISPR. Genome Biol. 2015;16(1):281. https://doi.org/10.1186/s13059-015-0843-6.CrossRefPubMedPubMedCentral

21.

Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40. https://doi.org/10.1093/bioinformatics/btp616.CrossRefPubMed

22.

Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357–60. https://doi.org/10.1038/nmeth.3317.CrossRefPubMedPubMedCentral

23.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078–9. https://doi.org/10.1093/bioinformatics/btp352.CrossRefPubMedPubMedCentral

24.

Anders S, Pyl PT, Huber W. HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9. https://doi.org/10.1093/bioinformatics/btu638.CrossRefPubMed

25.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50. https://doi.org/10.1073/pnas.0506580102.CrossRefPubMedPubMedCentral

26.

Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45(D1):D353–61. https://doi.org/10.1093/nar/gkw1092.CrossRefPubMed

27.

Park H, Cho S-Y, Kim H, Na D, Han JY, Chae J, et al. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer. Proc Natl Acad Sci. 2015;112(40):12492–7. https://doi.org/10.1073/pnas.1507491112.CrossRefPubMedPubMedCentral

28.

Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25(14):1754–60. https://doi.org/10.1093/bioinformatics/btp324.CrossRefPubMedPubMedCentral

29.

Fromer M, Moran JL, Chambert K, Banks E, Bergen SE, Ruderfer DM, et al. Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet. 2012;91(4):597–607. https://doi.org/10.1016/J.AJHG.2012.08.005.29.CrossRefPubMedPubMedCentral

30.

Okada M. Regulation of the SRC family kinases by Csk. Int J Biol Sci. 2012;8(10):1385–97. https://doi.org/10.7150/ijbs.5141.CrossRefPubMedPubMedCentral

31.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(D1):D447–52. https://doi.org/10.1093/nar/gku1003.CrossRefPubMed

32.

Okines AFC, Cunningham D. Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer. Ther Adv Gastroenterol. 2012;5(5):301–18. https://doi.org/10.1177/1756283X12450246.CrossRef

33.

FDA News Release: FDA approves new treatment for adults with relapsed follicular lymphoma. Food and Drug Administration. (Release date, September 14, 2017) https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576129.htm. Accessed 20 Dec 2018.

34.

Eroglu Z, Ribas A. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther Adv Med Oncol. 2016;8(1):48–56. https://doi.org/10.1177/1758834015616934.CrossRefPubMedPubMedCentral

35.

Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol. 2018;834:188–96. https://doi.org/10.1016/J.EJPHAR.2018.07.034.CrossRefPubMed

36.

Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21(41):6255–63. https://doi.org/10.1038/sj.onc.1205794.CrossRefPubMed

37.

Biller JR, Elajaili H, Meyer V, Rosen GM, Eaton SS, Eaton GR. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther. 2012;236(3):47–56. https://doi.org/10.1016/j.jmr.2013.08.006.CrossRef

38.

Zhang Z, Wang J, Ji D, Wang C, Liu R, Wu Z, et al. Functional genetic approach identifies MET, HER3, IGF1R, INSR pathways as determinants of Lapatinib unresponsiveness in HER2-positive gastric cancer. Clin Cancer Res. 2014;20(17):4559–73. https://doi.org/10.1158/1078-0432.CCR-13-3396.CrossRefPubMed

39.

Lu Y, Yu Q, Liu JH, Zhang J, Wang H, Koul D, et al. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem. 2003;278(41):40057–66. https://doi.org/10.1074/jbc.M303621200.CrossRefPubMed

40.

Ebbesen SH, Scaltriti M, Bialucha CU, Morse N, Kastenhuber ER, Wen HY, et al. Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas. Proc Natl Acad Sci U S A. 2016;113(11):3030–5. https://doi.org/10.1073/pnas.1523693113.CrossRefPubMedPubMedCentral

41.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4. https://doi.org/10.1158/2159-8290.CD-12-0095.CrossRefPubMed

42.

Cizkova M, Dujaric M-E, Lehmann-Che J, Scott V, Tembo O, Asselain B, et al. Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Br J Cancer. 2013;108(9):1807–9. https://doi.org/10.1038/bjc.2013.164.CrossRefPubMedPubMedCentral

43.

Eichhorn PJA, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68(22):9221–30. https://doi.org/10.1158/0008-5472.CAN-08-1740.CrossRefPubMedPubMedCentral

44.

de Bruin EC, Cowell C, Warne PH, Jiang M, Saunders RE, Melnick MA, et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 2014;4(5):606–19. https://doi.org/10.1158/2159-8290.CD-13-0741.CrossRefPubMedPubMedCentral

45.

Gibney GT, Smalley KSM. An unholy alliance: cooperation between BRAF and NF1 in melanoma development and BRAF inhibitor resistance. Cancer Discov. 2013;3(3):260–3. https://doi.org/10.1158/2159-8290.CD-13-0017.CrossRefPubMedPubMedCentral

46.

Singh A, Misra V, Thimmulappa RK, et al. Dysfunctional KEAP1–NRF2 interaction in Non-Small-Cell lung cancer. Meyerson M, ed. Plos Med. 2006;3(10):e420. https://doi.org/10.1371/journal.pmed.0030420.CrossRefPubMedPubMedCentral

47.

Wang X-J, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008;29(6):1235–43. https://doi.org/10.1093/carcin/bgn095.CrossRefPubMedPubMedCentral

48.

Nakaso K, Yano H, Fukuhara Y, Takeshima T, Wada-Isoe K, Nakashima K. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 2003;546(2–3):181–4. https://doi.org/10.1016/S0014-5793(03)00517-9.CrossRefPubMed

Title: A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer
Authors: Gang Ning
Qihui Zhu
Wonyoung Kang
Hamin Lee
Leigh Maher
Yun-Suhk Suh
Michael Michaud
Mayerlin Silva
Jee Young Kwon
Chengsheng Zhang
Charles Lee
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Gastric Cancer
Gastric Cancer
Lapatinib
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08283-9

2024 ASCO Annual Meeting Coverage

Highlights of the Day: Breast cancer – metastatic

Breast Cancer Video

In this session, Dr. Wolff provides his key takeaways from the data presented in the metastatic breast cancer oral abstract session at ASCO 2024.

Watch now

Highlights of the Day: Gynecologic cancer

Gynecologic Cancer Video

Highlights of the Day: Breast Cancer – local/regional/adjuvant

Breast Cancer Video

Neoadjuvant dual immunotherapy improves melanoma outcomes

04-06-2024 Melanoma News

» View more highlights on the ASCO 2024 congress hub page

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Image Credits

ASCO 2024 | Highlights of the Day: Breast cancer – metastatic/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Gynecologic Cancer/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Breast Cancer – local/regional/adjuvant/© 2024 American Society of Clinical Oncology, all rights reserved., Melanoma/© selvanegra / Getty Images / iStock, Antibody drug conjugated with cytotoxic payload/© Love Employee / Getty images / iStock

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Integrative genomic expression analysis reveals stable differences between lung cancer and systemic sclerosis

The viral expression and immune status in human cancers and insights into novel biomarkers of immunotherapy

CD36 promotes vasculogenic mimicry in melanoma by mediating adhesion to the extracellular matrix

High vimentin expression with E-cadherin expression loss predicts a poor prognosis after resection of grade 1 and 2 pancreatic neuroendocrine tumors

Real world duration of curative intent breast, colorectal, non-small cell lung, and prostate cancer treatment