Danica Amirtham

Background:  Lung cancer remains one of the leading causes of cancer mortality worldwide, largely due to the lack of effective early screening, delayed onset of symptoms, and heterogeneity of tumors.^1,2 Majority of the lung cancer cases are non-small cell lung cancer (NSCLC), and typically derived from mutations in the epidermal growth factor receptor.¹ These tumors are initially sensitive to targeted therapies like EGFR tyrosine kinase inhibitors  (EGFR-TKIs). However, despite initial clinical response, the vast majority of patients eventually develop acquired resistance to EGFR-TKIs, leading to treatment failure and disease progression. Understanding the various adaptive mechanisms of tumors becomes vital in development of effective treatment. Many resistance mechanisms coincide with the PI3K/AKT pathway, particularly AXL and AURKB proteins, which are explored as a potential therapeutic target.^3,4 The heterogeneity of the tumors also places importance on a multi-targeted approach to therapy as well as emphasizes a need for continuous monitoring.⁵

Research Objectives:  In this narrative review, we examined resistance mechanisms involving the PI3K/AKT pathway in lung cancer, highlighting the heterogeneity of resistance and discussing the potential integration of liquid biopsy.

Methods:  Peer-reviewed articles were identified using PubMed and key search terms included: “EGFR resistance lung cancer,” “PI3/AKT” “Aurora B kinase apoptosis,” and “liquid biopsy EGFR mutations.” Selection was limited to articles from 2020–2024.

Results:  Studies show that AXL senses cellular stress and DNA damage.³ This indicates that under  EGFR-TKI medication stress AXL becomes activated, which allows cancer cells to pause and adapt. RAD18 is a key DNA repair protein downstream that facilitates translesion synthesis(TLS).³ TLS enables DNA replication to proceed despite damage using low-fidelity polymerases driving mutagenesis. Under stress cancer cells are shown to switch from high fidelity polymerases to low fidelity.³ AXL also plays a key role in transitioning cells from a persistent to resistant state by allowing cells to remain metabolically active and mutationally plastic.³ Separately, AURKB, continues to phosphorylate and degrade BIM even in the presence of EGRF-TKI which suppresses ERK signaling.⁴ Degradation of BIM leads to reduced apoptosis seen in the high AURKB environment of cancer cells.⁴ Additionally clinical trials have confirmed that many tumors have more than one resistance mechanism simultaneously.⁵ The heterogeneity is seen within a given tumor or the evolution of the original vs the metastatic tumor. This highlights the importance of continuous monitoring, which can now be obtained using an emerging non-invasive technique called liquid biopsy. Liquid biopsy uses ctDNA to characterize tumors.²

Conclusion:  AXL and AURKB are compelling therapeutic targets that are shown to prevent resistance and the continued proliferation of cancer cells.  AXL promotes mutagenesis and genetic plasticity, while AURKB allows for continued survival under apoptotic pressure.^3,4 Taking into consideration the heterogeneity of the tumors it can be highly beneficial to target multiple pathways.⁵ Liquid biopsy can further be used to monitor the evolving mechanisms causing resistance in the patient, enabling proper adjustment to treatment strategies that can improve therapeutic efficacy.

Works Cited:

1. Bade BC, Dela Cruz CS. Lung cancer 2020: Epidemiology, etiology, and prevention. Clin Chest Med. 2020;41(1):1-24. doi:10.1016/j.ccm.2019.10.001
2. Casula M, Pisano M, Paliogiannis P, et al. Comparison between three different techniques for the detection of EGFR mutations in liquid biopsies of patients with advanced stage lung adenocarcinoma. Int J Mol Sci. 2023;24(7):6410. Published March 29, 2023. doi:10.3390/ijms24076410
3. Noronha A, Nishanth Belugali Nataraj, Joo Sang Lee, et al. AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer. Cancer Discovery. 2022;12(11):2666-2683. doi:10.1158/2159-8290.cd-22-0111
4. Tanaka K, Yu HA, Yang S, et al. Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell. 2021;39(9):1245-1261.e6. doi:10.1016/j.ccell.2021.07.006
5. Roper N, Brown A, Wei JS, et al. Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer. Cell Reports Medicine. 2020;1(1):100007-100007. doi:10.1016/j.xcrm.2020.100007
6. Midthun DE. Clinical manifestations of lung cancer. UpToDate. Published July 31, 2024. https://www.uptodate.com/contents/clinical-manifestations-of-lung-cancer
7. Nooreldeen R, Bach H. Current and future development in lung cancer diagnosis. Int J Mol Sci. 2021;22(16):8661. Published August 12, 2021. doi:10.3390/ijms22168661
8. Hao P, Huang Y, Peng J, et al. IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways. Experimental Cell Research. 2021;403(2):112615. doi:10.1016/j.yexcr.2021.112615
9. Xu X, Liu Y, Gong Q, et al. PARP1 promotes EGFR-TKI drug-resistance via PI3K/AKT pathway in non-small-cell lung cancer. Cancer chemotherapy and pharmacology. 2024;94(2):209-221. doi:1007/s00280-024-04668-2