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Open research questions in Lung Cancer Treatments and Mutations

228 unresolved questions extracted from the limitations and future-work sections of 801 Lung Cancer Treatments and Mutations papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The emergence of drug resistance to third-generation EGFR inhibitors like osimertinib. The clinical resistance to osimertinib through the EGFR C797S mutation. The need to develop effective fourth-generation EGFR inhibitors that can overcome this resistance.

    Comparative profiling of osimertinib and fourth-generation EGFR inhibitors on EGFR-mutant proteins and cell lines · 2026 · DOI

  • No limitations are explicitly stated in the text. The study only evaluated a limited number of fourth-generation EGFR inhibitors. The study used a specific cell line and panel of cancer cell lines.

    Comparative profiling of osimertinib and fourth-generation EGFR inhibitors on EGFR-mutant proteins and cell lines · 2026 · DOI

  • Substantial heterogeneity among included studies. Potential small-study effects influencing the observed association between RASi use and survival outcomes. Limited data on the association between RASi use and survival outcomes in specific subgroups of lung cancer patients.

    Renin–angiotensin system inhibitor use and survival outcomes in lung cancer: a systematic review and meta-analysis · 2026 · DOI

  • Substantial heterogeneity remained in several subgroups, - Evidence of small-study effects for OS, - The robustness of the OS association remains uncertain

    Renin–angiotensin system inhibitor use and survival outcomes in lung cancer: a systematic review and meta-analysis · 2026 · DOI

  • small sample size (single case report), - limited follow-up time, - no control group, - potential risk of lung injury with T-DXd, - no consensus on optimal HER2 testing methodology in NSCLC

    HER2 amplification as a resistance mechanism to osimertinib and its successful treatment with trastuzumab deruxtecan: a case report · 2026 · DOI

  • further studies on the efficacy and safety of T-DXd in NSCLC with HER2 amplification, - investigation of combination therapy with osimertinib and T-DXd, - development of optimal HER2 testing methodology in NSCLC, - research on the mechanisms of HER2 amplification as a resistance mechanism to osimertinib

    HER2 amplification as a resistance mechanism to osimertinib and its successful treatment with trastuzumab deruxtecan: a case report · 2026 · DOI

  • The challenge of analyzing Trop-2 protein expression in NSCLC due to limited understanding of its expression profile. The need to develop effective treatments for NSCLC, given the low 5-year survival rate of advanced disease. The challenge of characterizing Trop-2 expression across multiple datasets and sample sets.

    Trop-2 expression in non–small cell lung cancer · 2025 · DOI

  • investigation of the efficacy of Trop-2-directed ADCs in NSCLC, - examination of Trop-2 expression in other types of cancer, - further analysis of the relationship between Trop-2 mRNA and protein expression

    Trop-2 expression in non–small cell lung cancer · 2025 · DOI

  • Conventional PCR techniques often fail to detect more than 50% of EGFR exon 20 insertion mutations, - Response heterogeneity may arise depending on the mutation's location within EGFR exon 20, - Limited activity of some TKIs against wild-type EGFR

    Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer · 2024 · DOI

  • Conventional tyrosine kinase inhibitors have limited efficacy against EGFR exon 20 insertions. There is a need for targeted agents that can effectively treat NSCLC with EGFR exon 20 insertions. Overcoming resistance mutations and improving central nervous system penetration remain significant challenges.

    Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer · 2024 · DOI

  • However, the mechanisms by which CDK4/6 upregulation promotes therapy resistance remain poorly defined.

    CDK4 or CDK6 upregulation induces DNA replication stress and genomic instability to cause EGFR targeted therapy resistance in lung cancer · 2026 · DOI

  • Continued collaborative efforts are warranted to refine treatment sequencing and translate emerging technologies into measurable patient benefit.

    AI-Driven precision targeted therapy for EGFR-mutant non-small cell lung cancer: From therapeutic evolution and resistance mechanisms to intelligent decision systems · 2026 · DOI

  • However, the optimal timing of brain radiotherapy (BRT) in combination with third-generation EGFR-TKIs remains uncertain.

    Brain radiotherapy synergizes with first-line, third-generation EGFR-TKIs in patients with EGFR-mutant NSCLC and treatment-naïve brain metastases: a multicenter real-world study · 2026 · DOI

  • Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized.

    Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer · 2025 · DOI

  • Prospective studies designed to compare neoadjuvant, adjuvant, and perioperative approaches and to assess the role of circulating biomarkers are warranted.

    Immune Checkpoint Inhibitors and Targeted Therapies in Early-Stage Non-Small-Cell Lung Cancer: State-of-the-Art and Future Perspectives · 2025 · DOI

  • Since resistance to osimertinib is poorly understood, the following review presents the overview of resistance mechanisms to osimertinib, methodological approaches for the resistance diagnosis, and the up-to-date treatment possibilities for overcoming the resistance process.

    Possibilities of Overcoming Resistance to Osimertinib in NSCLC Patients with Mutations in the EGFR Gene · 2025 · DOI

  • Cuproptosis, a novel form of copper-dependent regulated cell death, 1 , 2 has shown promise in overcoming radioresistance, 3 but its potential in targeted therapy remains unexplored.

    Induction of cuproptosis enhances sensitivity and overcomes resistance to osimertinib in lung cancer · 2025 · DOI

  • However, the risk of cancer therapy–related cardiovascular diseases (CTRCVDs) is underrecognized, particularly comparing second‐generation ALK–tyrosine kinase inhibitors alectinib and brigatinib to the third‐generation tyrosine kinase inhibitor lorlatinib, which offers the longest progression‐free survival.

    Increased Cardiovascular Risk With Lorlatinib in Patients With ALK‐Mutated Lung Cancer: A Real‐World Comparative Study · 2025 · DOI

  • However, there was a significant selection effect and outcomes in routine care are rarely reported, with only one published case series.

    P17.28.B SURVIVAL IN MGMT-METHYLATED GBM TREATED WITH COMBINED TEMOZOLOMIDE AND LOMUSTINE IN ROUTINE CARE: AN UPDATED AND EXPANDED UK RETROSPECTIVE MULTI-CENTRE COHORT STUDY · 2025 · DOI

  • While past in vitro studies identified diverse drivers of drug-tolerant persistence to EGFR TKIs in NSCLC, the resultant phenotypic plasticity is not well understood and in vivo models of persistence are lacking.

    A Path to Persistence after EGFR Inhibition · 2024 · DOI

  • Despite this, preclinical strategies designed to exploit growth within the context of invasion are lacking.

    Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1 -Mutant Lung Cancer · 2024 · DOI

  • Nevertheless, comprehensive NTRK profiling at the pan-cancer genomic level and real-world studies pertaining to the adverse events of NTRK inhibitors are lacking.

    From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis · 2024 · DOI

  • However, the nature of cardiac remodeling and associated risk factors remains incompletely understood.

    Cardiac events and dynamic echocardiographic and electrocardiogram changes following osimertinib treatment in lung cancer · 2024 · DOI

  • Whether these improvements translate into the clinic setting has not been studied yet.

    Real-World Survival Impact of New Treatment Strategies for Lung Cancer: A 2000–2020 French Cohort · 2024 · DOI

  • Identification of therapeutic targets and prognostic biomarkers is still lacking.

    Transcriptomic Profiling for Prognostic Biomarkers in Early-Stage Squamous Cell Lung Cancer (SqCLC) · 2024 · DOI

Most-cited papers in Lung Cancer Treatments and Mutations

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228 open questions have been extracted from the limitations and future-work passages of 801 Lung Cancer Treatments and Mutations papers in our 4.5M-paper local library. Each one below links back to the study that raised it, so you can read the original claim in context.

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