Research Progress on the Role of Bypass Activation Mechanisms in Resistance to Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Nov 25

PMID 39582541

Authors

Ziyang Jiang

Zhihan Gu

Xiaomin Yu

Tao Cheng

Bofu Liu

Affiliations

Soon will be listed here.

Abstract

The clinical application of small molecule tyrosine kinase inhibitors (TKIs) has significantly improved the quality of life and prognosis of patients with non-small cell lung cancer (NSCLC) carrying driver genes. However, resistance to TKI treatment is inevitable. Bypass signal activation is one of the important reasons for TKI resistance. Although TKI drugs inhibit downstream signaling pathways of driver genes, key signaling pathways within tumor cells can still be persistently activated through bypass routes such as MET gene amplification, EGFR gene amplification, and AXL activation. This continuous activation maintains tumor cell growth and proliferation, leading to TKI resistance. The fundamental strategy to treat TKI resistance mediated by bypass activation involves simultaneously inhibiting the activated bypass signals and the original driver gene signaling pathways. Some clinical trials based on this combined treatment approach have yielded promising preliminary results, offering more treatment options for NSCLC patients with TKI resistance. Additionally, early identification of resistance mechanisms through liquid biopsy, personalized targeted therapy against these mechanisms, and preemptive targeting of drug-tolerant persistent cells may provide NSCLC patients with more sustained and effective treatment.

References

Zeng L, Yang N, Zhang Y . GOPC-ROS1 Rearrangement as an Acquired Resistance Mechanism to Osimertinib and Responding to Crizotinib Combined Treatments in Lung Adenocarcinoma. J Thorac Oncol. 2018; 13(7):e114-e116. DOI: 10.1016/j.jtho.2018.02.005. View

Mackiewicz M, Huppi K, Pitt J, Dorsey T, Ambs S, Caplen N . Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA. Breast Cancer Res Treat. 2011; 130(2):663-79. PMC: 3381742. DOI: 10.1007/s10549-011-1690-0. View

Wang Y, Xia H, Zhuang Z, Miao L, Chen X, Cai H . Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer. Cell Death Dis. 2014; 5:e1227. PMC: 4047906. DOI: 10.1038/cddis.2014.186. View

Shaw A, Bauer T, de Marinis F, Felip E, Goto Y, Liu G . First-Line Lorlatinib or Crizotinib in Advanced -Positive Lung Cancer. N Engl J Med. 2020; 383(21):2018-2029. DOI: 10.1056/NEJMoa2027187. View

Tulchinsky E, Demidov O, Kriajevska M, Barlev N, Imyanitov E . EMT: A mechanism for escape from EGFR-targeted therapy in lung cancer. Biochim Biophys Acta Rev Cancer. 2018; 1871(1):29-39. DOI: 10.1016/j.bbcan.2018.10.003. View

Planchard D, Loriot Y, Andre F, Gobert A, Auger N, Lacroix L . EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015; 26(10):2073-8. DOI: 10.1093/annonc/mdv319. View

Mehlman C, Cadranel J, Rousseau-Bussac G, Lacave R, Pujals A, Girard N . Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study. Lung Cancer. 2019; 137:149-156. DOI: 10.1016/j.lungcan.2019.09.019. View

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

Okura N, Nishioka N, Yamada T, Taniguchi H, Tanimura K, Katayama Y . ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in -Mutated Non-Small Cell Lung Cancer. Clin Cancer Res. 2020; 26(9):2244-2256. DOI: 10.1158/1078-0432.CCR-19-2321. View

10.

Tanizaki J, Okamoto I, Okabe T, Sakai K, Tanaka K, Hayashi H . Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer. Clin Cancer Res. 2012; 18(22):6219-26. DOI: 10.1158/1078-0432.CCR-12-0392. View

11.

Ma P, Jagadeeswaran R, Jagadeesh S, Tretiakova M, Nallasura V, Fox E . Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 2005; 65(4):1479-88. DOI: 10.1158/0008-5472.CAN-04-2650. View

12.

Hsu J, Hung M . The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016; 35(4):575-588. PMC: 5215954. DOI: 10.1007/s10555-016-9649-6. View

13.

Govindan R, Ding L, Griffith M, Subramanian J, Dees N, Kanchi K . Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012; 150(6):1121-34. PMC: 3656590. DOI: 10.1016/j.cell.2012.08.024. View

14.

Scaltriti M, Elkabets M, Baselga J . Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy. Clin Cancer Res. 2016; 22(6):1313-7. PMC: 4957976. DOI: 10.1158/1078-0432.CCR-15-1458. View

15.

Liu Y, Tsai M, Wu S, Chang T, Tsai T, Gow C . Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer. Int J Cancer. 2019; 145(6):1609-1624. DOI: 10.1002/ijc.32487. View

16.

Wilson F, Johannessen C, Piccioni F, Tamayo P, Kim J, Van Allen E . A functional landscape of resistance to ALK inhibition in lung cancer. Cancer Cell. 2015; 27(3):397-408. PMC: 4398996. DOI: 10.1016/j.ccell.2015.02.005. View

17.

Planchard D, Janne P, Cheng Y, Yang J, Yanagitani N, Kim S . Osimertinib with or without Chemotherapy in -Mutated Advanced NSCLC. N Engl J Med. 2023; 389(21):1935-1948. DOI: 10.1056/NEJMoa2306434. View

18.

Brand T, Iida M, Stein A, Corrigan K, Braverman C, Luthar N . AXL mediates resistance to cetuximab therapy. Cancer Res. 2014; 74(18):5152-64. PMC: 4167493. DOI: 10.1158/0008-5472.CAN-14-0294. View

19.

Chen J, Yang H, Teo A, Amer L, Sherbaf F, Tan C . Genomic landscape of lung adenocarcinoma in East Asians. Nat Genet. 2020; 52(2):177-186. DOI: 10.1038/s41588-019-0569-6. View

20.

Zhu X, Chen L, Liu L, Niu X . EMT-Mediated Acquired EGFR-TKI Resistance in NSCLC: Mechanisms and Strategies. Front Oncol. 2019; 9:1044. PMC: 6798878. DOI: 10.3389/fonc.2019.01044. View