KRAS-Targeting Agents in Cancer: A Bibliometric Analysis of Global Research Trends and Emerging Hotspots from 2006 to 2026

Technical Summary: KRAS-Targeting Agents in Cancer (2006–2026)

Problem Statement
For decades, the KRAS oncogene represented a central paradox in oncology: it was a primary driver in lung, colorectal, and pancreatic cancers, yet it was considered "undruggable" due to its smooth molecular surface lacking defined binding pockets and its picomolar affinity for GTP/GDP. Early therapeutic strategies relied on indirect approaches, such as farnesyltransferase inhibition and downstream pathway blockade, which failed to yield durable, selective therapies. While the discovery of covalent allosteric inhibitors targeting the KRAS G12C switch-II pocket (Ostrem et al., 2013) marked a paradigm shift, the field has rapidly expanded with new agents, resistance mechanisms, and allele-specific targets. There is a need to characterize the global evolution of this research landscape, moving from indirect pathway biology to direct mutant inhibition, and to identify emerging intellectual hotspots and collaboration patterns.

Methodology
This study employed a bibliometric and science-mapping approach to analyze the global research landscape of KRAS-targeted therapy from 2006 to 2026.

• Data Source: Records were retrieved from the Web of Science Core Collection (WoSCC) on July 2, 2026.
• Search Strategy: A comprehensive topic-field search combined terms for KRAS (including variants like G12C, G12D) with therapeutic terms (inhibitors, targeted therapy, specific drug names like sotorasib, adagrasib, AMG 510, etc.) and cancer-related terms.
• Inclusion Criteria: The analysis was restricted to peer-reviewed articles and reviews in English. Meeting abstracts and non-article/review documents were excluded.
• Analytical Tools: Data processing and visualization were conducted using Bibliometrix/Biblioshiny (R), VOSviewer, and Microsoft Excel.
• Metrics: The study evaluated annual publication output, citation patterns, country/institutional productivity, author networks, keyword co-occurrence, co-citation structures, and trend topics.

Key Contributions and Results
The final dataset comprised 3,265 publications (2,675 articles and 590 reviews) spanning 723 sources and citing 88,334 references.

1. Publication Trajectory: Annual output increased gradually through the 2010s but accelerated significantly after 2020, peaking in 2025. This acceleration correlates with the clinical translation of direct KRAS G12C inhibitors. The 2026 data shows a partial decline, attributed to incomplete indexing for the current calendar year.
2. Geographic and Institutional Landscape:
   • Production: The USA and China lead in country-affiliation occurrence frequency. The USA maintains the highest citation impact, while China shows a steep recent rise in production volume.
   • Institutions: Leading contributors include major translational cancer centers (e.g., MD Anderson, Memorial Sloan Kettering, Dana-Farber) and industry-linked research environments (e.g., Genentech).
   • Collaboration: The field is highly collaborative, with an average of 11.5 co-authors per document and nearly 30% international co-authorship. The network consists of multiple overlapping communities rather than a single centralized group.
3. Intellectual Structure and Evolution:
   • Thematic Shift: Keyword and trend-topic analyses reveal a distinct temporal shift. Early literature (pre-2010s) focused on farnesyltransferase inhibitors, synthetic lethality, and downstream pathway signaling. Post-2018, the focus shifted decisively toward allele-specific targeting (KRAS G12C), specific drug names (AMG 510, MRTX849), efficacy, and resistance mechanisms.
   • Emerging Hotspots: Recent trends indicate a move beyond G12C toward KRAS G12D, pan-KRAS inhibition, and RAS(ON) strategies, alongside a sustained focus on acquired resistance.
4. Citation Impact: The most cited documents reflect the field's history:
   • Foundational: Barbie et al. (2009) and Engelman et al. (2008) represent early synthetic vulnerability and pathway-based approaches.
   • Chemical Biology: Ostrem et al. (2013), Janes et al. (2018), and Canon et al. (2019) established the chemical basis for G12C inhibition.
   • Clinical Translation: Hong et al. (2020), Skoulidis et al. (2021), and subsequent studies on sotorasib and adagrasib anchor the clinical efficacy and resistance literature.

Significance and Claims
The authors position this work as the first bibliometric analysis specifically focused on pharmacological KRAS inhibitors. The study claims to:

• Map the Evolution: Demonstrate the transition of KRAS research from a "therapeutically elusive" pathway-centered field to a rapidly expanding precision oncology domain driven by direct mutant inhibition.
• Identify Frontiers: Highlight that current research frontiers are defined by overcoming resistance biology and expanding targeting to non-G12C alleles (e.g., G12D) and broader RAS-directed strategies.
• Clarify Scope: Emphasize that bibliometric patterns serve as indicators of research activity, intellectual structure, and scientific attention. The authors explicitly state that these findings do not constitute evidence of therapeutic efficacy or methodological quality.
• Contextualize Limitations: The study acknowledges that the search strategy captures both direct inhibitors and indirect pathway biology (e.g., KRAS as a biomarker for anti-EGFR therapy), which enriches the historical context but requires careful interpretation of thematic shifts.

In conclusion, the paper asserts that the field has consolidated around direct mutant KRAS inhibition but is actively diversifying to address resistance and broader allele targeting, with research activity heavily concentrated in the USA and China within major translational cancer centers.