111 Research Progress on Resistance Mechanisms and Post- Resistance Treatment of Targeted Therapy in Non-Small Cell Lung Cancer Ziyuan Gao 1, †, *, Yuzhu Chen 2, † 1 School of Medicine, Xi'an Jiaotong University, Xi’an Shaanxi, 710049, China 2 Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China * Corresponding Author: Ziyuan Gao (Email: gzy042813@163.com) † Two authors have made equal contributions to this article Abstract. Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality worldwide, and about 60% of the advanced cancer stage patients carry particular molecular mutations that model potential targets in terms of targeted therapy. Gene mutations such as EGFR, MET, and ALK are key drivers of NSCLC. Targeted drugs against these mutations, including EGFR- TKIs, MET-TKIs, and ALK-TKIs, have significantly improved patient prognosis. However, acquired resistance remains a significant challenge, with mechanisms involving secondary target mutations, bypass activation, and phenotypic transformation. This review summarizes the resistance mechanisms of targeted therapy in NSCLC and corresponding therapeutic strategies, aiming to provide new insights for post-resistance treatment. Keywords: Non-small Cell Lung Cancer (NSCLC); Targeted Therapy; EGFR-TKIs; Acquired Resistance. 1. Introduction Lung cancer is the most frequent cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) represents 80%85 of the cases [1]. Molecular advances have driven targeted therapy forward; around 60% of advanced NSCLC patients carry actionable mutations [2]. The most prevalent, which occur in 50 percent of Asian and 10 percent to 16.6 percent of Caucasian patients, are EGFR mutations [3]. EGFR-TKIs have markedly improved outcomes, evolving through generations to counter resistance—notably the T790M mutation with third-generation agents. However, acquired resistance remains a major clinical challenge. MET alterations occur in ∼7% of NSCLC cases, with Type I MET-TKIs offering targeted inhibition [4]. ALK rearrangements, more common in young non-smokers, promote tumorigenesis via downstream signaling [5]. ALK-TKIs have also advanced generationally. Despite improved outcomes, acquired resistance—through secondary mutations, bypass activation, or phenotypic transformation—limits long-term efficacy. These mechanisms are important to understand and come up with post-resistance. This review is a summary of resistance in NSCLC targeted therapy and responsive therapies. 2. Resistance Mechanisms 2.1 Resistance Mechanisms to EGFR-TKIs Resistance to EGFR-TKIs is classified as primary or acquired. Acquired resistance further divides into EGFR-dependent and independent mechanisms. EGFR-dependent resistance primarily involves secondary mutations reducing drug binding affinity, notably T790M conferring resistance to first- and second-generation TKIs [6], and C797S driving resistance to third-generation agents like osimertinib [7]. EGFR-independent resistance commonly arises through bypass activation, such as MET amplification (5%–10% of cases) activating PI3K-AKT via HER3 dimerization [8-10], or other 112 mechanisms including HER2 amplification, RAS-MAPK pathway activation, and oncogenic fusions. Histological transformation, e.g., to SCLC, occurs in 5%–10% of patients, often with RB1/TP53 loss [8-11]. 2.2 Resistance Mechanisms to Other Targeted Drugs For MET-TKIs, resistance involves MET-dependent mutations (e.g., D1228, Y1230) or amplification, and MET-independent mechanisms like RAS/MAPK or PI3K/AKT activation or EGFR/HER2 bypass [12, 13]. ALK-TKI resistance includes ALK-dependent compound mutations (e.g., G1202R+L1196M) and ALK-independent bypass activation; the 2024 ASCO CROWN study reported lorlatinib resistance primarily involving MAPK/PI3K/RTK pathway alterations and cell cycle abnormalities [14]. Figure 1. illustrates the acquired resistance mechanisms to EGFR-TKIs, categorized into EGFR-dependent and independent. Mutations (e.g., T790M, C797S) are part of the EGFR- dependent mechanisms, which decrease drug binding. EGFR-independent pathways include bypass resistance (ex, MET amplification, HER2 amplification, ALK fusion) and aberrant downstream signalling (ex, PI3K/AKT/mTOR, RAS/RAF/MEK/ERK), which facilitates the survival of cancer cells, their growth, and anti-apoptosis. It is also important that there should be a histological change (e.g., NSCLC to SCLC/SCC). 3. Post-Resistance Treatment 3.1 Treatment After EGFR-TKI Resistance EGFR-TKIs are currently used as first-line therapy of advanced MSG of the lung (ETS), which is positive on tested for epidermal growth factor receptor (EGFR). The progression that occurs after the resistance can be categorised into oligoprogression, intracranial progression, and extensive progression. The first Asia-Pacific consensus, based on the third-generation resistance of the two types of origin medicine, of the use of drugs targeted at a gene controller (EGFR-TKI), recommendation by the guidelines of China in the medical sciences (CSCO) recommends customized mode of the method. 113 3.1.1 Strategies for Oligoprogression and Intracranial Progression For oligoprogression, local therapies (e.g., radiotherapy, surgery, radiofrequency ablation) combined with continued EGFR-TKIs are recommended, with studies showing improved PFS and OS compared to EGFR-TKIs alone. For intracranial progression, treatment (surgery or systemic therapy) is guided by the number and size of brain metastases. 3.1.2 Strategies for Extensive Progression Biopsies after third-generation EGFR-TKI resistance identify mechanisms in some patients, but 30%-50% remain unclear. 3.1.2.1 Treatment for Defined Resistance Mechanisms For defined resistance mechanisms, treatment strategies are highly targeted. Fourth-generation EGFR-TKIs, including BDTX-1535, are active in EGFR-dependent resistance, which includes the C797S mutation, where the phase II trial (NCT05256290) recorded a response rate (ORR) of 42% [15]. The conventional treatment is platinum chemotherapy. For EGFR-independent resistance, combination therapies are selected based on the specific mechanism: osimertinib combined with MET-TKIs is recommended for MET amplification [16, 17]; trastuzumab deruxtecan (T-DXd) has shown significant activity against HER2 amplification, as evidenced in the DESTINY-Lung02 trial [18]; dabrafenib plus trametinib is an established strategy for BRAF V600E mutations, with five-year follow-up data showing 5-year OS rates of 19% in pretreated and 22% in untreated patients [19, 20]. Combinations targeting downstream pathways are under active investigation. 3.1.2.2 Treatment for Undefined Resistance Mechanisms Another future strategy with respect to patients of unspecified resistance mechanisms is antibody- drug conjugates (ADCs). In a phase II trial (HERTHENA-Lung01), HER23-DXd (patritumab deruxtecan) was discovered to have an ORR and a median progression-free survival (mPFS) of 29.8 and 5.5 months, respectively [21].ADCs targeting TROP2, including datopotamab deruxtecan (Dato- DXd), have also shown clinical response in phase III trials. The conventional chemotherapy based on platinum has its limitations, but it is still at the backbone of treatment. The combination of lazertinib, amivantamab, and chemotherapy showed potential in a small study [22], while immunotherapy combined with EGFR-TKIs is not recommended due to safety concerns [23]. Regimens combining immunotherapy, chemotherapy, and anti-angiogenesis, such as the ABCP regimen in IMpower150 [24] and sintilimab-based combinations in ORIENT-31 [25], have shown efficacy in selected populations. 3.2 Treatment After Other TKI Resistance Strategies for MET-TKI and ALK-TKI resistance reference EGFR-TKI approaches, tailored to progression patterns and mechanisms. 3.2.1 Treatment After MET-TKI Resistance Management depends on the resistance type and clinical context. MET-dependent resistance (20%-35% of cases) [12, 13] may respond to sequential MET-TKIs, leveraging differential sensitivity between type I/II inhibitors [29]. The VISION trial confirmed tepotinib's efficacy in METex14- mutant NSCLC [30]. MET-independent resistance involves alternative pathways (e.g., RAS/MAPK, PI3K/AKT) or bypass activation (e.g., EGFR/HER2) [12, 13, 29, 31], potentially requiring combination strategies. For undefined mechanisms (25%-47%), platinum chemotherapy, immunotherapy, or anti-angiogenic therapy are standard options. 114 Table 1. Data summary of clinical trials in EGFR mutant metastatic NSCLC cases progressing on EGFR inhibitors Generation Resistance type Reference Study name Phase Treatment arm Efficacy Safety First/Second Generation T790M [26] APOLLO (NCT02981108) Ⅱ Almonertinib mPFS:12.4mo ORR:68.9% DCR:93.4% The incidence of grade 3 and above adverse events is low, and the safety is good. Third Generation C797S [15] NCT05256290 Ⅱ BDTX-1535 ORR:42% Most AEs are mild or moderate, and the researchers did not observe new safety signals. MET [16] ORCHARD Ⅱ osimertinib + savolitinib ORR:41% Grade ≥ 3 AE: 30% SAE: 30% [17] INSIGHT2 Ⅱ osimertinib + tepotinib mPFS:5.6 mo ORR:50% mOS:17.8mo Grade ≥ 3 AE: 34% SAE: 29% HER2 [18] Destiny-Lung02 (NCT04644237) Ⅱ T-DXd, DS- 8201 mPFS: 5.4mg/kg group:10.0mo 6.4mg/kg group:12.9mo ORR: 5.4mg/kg group:49% 6.4mg/kg group:56% mOS: 5.4mg/kg group:19.0mo 6.4mg/kg group:17.3mo Grade ≥ 3 AE: 5.4mg/kg group:39.6% 6.4mg/kg group:60.0% BRAF [19, 20, 27] BRF113928 Ⅱ A:Dabrafenib monotherapy B:Dabrafenib+ Trametinib (treated patients) C:Dabrafenib+ Trametinib (untreated patients) mPFS: A:5.5mo B:9.7mo C:10.9mo ORR: A:33% B:63.2% C:64% A: Common adverse events include fever, fatigue, nausea, and skin-related toxicities. B: Adverse events of combination therapy include fever, diarrhea, nausea, and rash, but they are generally controllable. C: Similar to cohort B. Undefined (HER3) [21] HERTHENA- Lung01 Ⅱ Patritumab deruxtecan(HE R3-DXd: U3- 1402) mPFS:5.5 mo ORR:29.8% mOS:11.9 mo Grade ≥ 3 TEAE: 64.9% SAE: 40% Undefined (TROP2) [28] TROPION- Lung01 Ⅲ A:Dato-Dxd B:Docetaxel mPFS: A: 4.4 mo B: 3.7 mo ORR: A:26.4% B:12.8% Grade ≥ 3 TRAE: A: 25%; B: 41% Serious TRAE: A: 10%; B: 12% Undefined [22] CHRYSALIS-2 Ib/II Amivantamab +Lazertinib +Carboplatin+ Pemetrexed The ORR reached 50%. The mPFS of 11 patients was 14.0 months. The most common grade ≥ 3 TEAEs include neutropenia (70%), thrombocytopenia (25%), and fatigue (25%). Undefined [24] IMpower150 Ⅲ Atezolizumab +Bevacizumab + Carboplatin+P aclitaxel (ABCP) Atezolizumab + Carboplatin+P aclitaxel (ACP) compared with the standard treatment Bevacizumab+ Carboplatin+P aclitaxel (BCP) mPFS: ACP:6.9mo BCP:6.9mo ABCP:10.2mo mOS: ACP:19.0mo BCP:18.1mo ABCP:29.4mo The incidences of grade 3-4 treatment-related adverse reactions were 56.8%, 55.8%, and 66.7% respectively. Undefined [25] ORIENT-31 Ⅲ A:sintilimab+I BI305+chemo B: sintilimab+ chemo C: chemo mPFS: A: 7.2 mo B: 5.5 mo C: 4.3 mo Grade ≥ 3 TRAE: A: 56% B: 41% C: 49% 115 3.2.2 Treatment After ALK-TKI Resistance Therapeutic strategies include sequential ALK-TKIs, combination therapies, or local intervention for oligoprogression. ALK-dependent resistance, particularly compound mutations involving G1202R, often retains sensitivity to next-generation agents like lorlatinib [32-36]. ALK-independent resistance, frequently involving bypass activation of MAPK, PI3K, or RTK pathways as reported in the 2024 ASCO CROWN study [14], may benefit from combination approaches such as ALK-TKIs with MEK inhibitors [37, 38]. Lorlatinib demonstrates notable intracranial activity [39], while brigatinib offers efficacy against specific mutations and bypass mechanisms [40]. Table 2. Data summary of clinical trials in MET and ALK mutant metastatic NSCLC cases progressing on MET and ALK inhibitors Generation Resistance type Reference Study name Phase Treatment arm Efficacy Safety First Generation MET- TKIs [41] NCT02414139 Ⅱ Capmatinib mPFS: Untreated patients: 9.69 mo Treated patients: 5.42 mo ORR: Untreated patients: 67.9% Treated patients: 40.6% mOS: Untreated patients: 20.82 mo Treated patients: 13.56 mo The safety is good, and most adverse events are mild to moderate. [30] NCT02864992 Ⅱ Tepotinib In the overall patient population, the ORR of Tepotinib was 51.4%, the mDOR was 18.0 months, the mPFS was 11.2 months, and the mOS was 19.6 months. Most adverse events are mild to moderate, and the incidence of grade 3 and above adverse events is 28.2%. Second Generation ALK- TKIs [39] NCT01970865 Ⅱ Lorlatinib Among patients who had received ≥ 1 second- generation ALK-TKI, the ORR reached 39.6%, the mDoR was 9.6 months, the mPFS was 6.6 months, and the mOS was 20.7 months. Common adverse events include hypercholesterolemia, hypertriglyceridemia, and peripheral neuropathy, and most of them are grade 1-2. [40] NCT02737501 Ⅱ Brigatinib Among patients who had received Crizotinib treatment, the ORR was 53%, and the mPFS was 16.7 months. Common adverse events include nausea, diarrhea, headache, and cough, and most of them are grade 1-2. 4. Discussions Targeted therapy significantly improves NSCLC management, yet acquired resistance remains a critical barrier. This review synthesizes key resistance mechanisms and evolving strategies, emphasizing that effective post-resistance treatment requires personalized approaches based on molecular profiling and clinical context. While next-generation TKIs, ADCs, and combination therapies show promise in extending survival, TKI-immunotherapy combinations remain limited by safety concerns and insufficient evidence. Beyond genetic alterations, emerging research highlights non-genetic mechanisms driving resistance. Drug-tolerant persister (DTP) cells evade therapy through epigenetic and signaling adaptations [42], while dysregulated ferroptosis, controlled by GPX4, SLC7A11, and NRF2, represents another key resistance pathway. Targeting DTP populations and modulating ferroptosis offer novel therapeutic opportunities to re-sensitise tumors to treatment. Future advances will depend on elucidating these mechanisms and integrating multidisciplinary strategies to overcome resistance and improve long-term outcomes. 116 5. Conclusion Targeted therapy has transformed NSCLC treatment by improving precision and patient outcomes, yet acquired resistance continues to limit long-term efficacy. This review summarizes the principal resistance mechanisms and corresponding strategies, underscoring the necessity of mechanism- guided therapy. The integration of next-generation TKIs, ADCs, and rational combinations provides promising paths to extend survival after resistance development. Future success will rely on targeting non-genetic mechanisms such as DTP cells and ferroptosis, advancing personalized multimodal strategies to overcome resistance and improve prognosis in NSCLC ultimately. Declarations Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Author Contributions Yuzhu Chen: Data curation; Resources; Writing, review & editing. Ziyuan Gao: Writing – review & editing. Competing Interests The authors declare that there is no conflict of interest. Availability of Data and Materials Not applicable. 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