Knowledge graph vs LLM
The same R&D question, answered by Mosaic's MCP tools over its oncology knowledge graph and by generic LLMs with web search. Answers are pre-recorded for reproducibility — every panel is timestamped and the methodology is published.
Which targets are implicated in resistance to EGFR inhibitors, and which of those are still development whitespace?
Operator commentary
Both LLMs surface the textbook bypass tracks (MET, HER2, AXL); Claude with web search additionally narrates SHP2, SOS1/SOS2, YES1, and FAK as whitespace candidates while GPT stays closer to fourth-gen TKI / AXL framing. Mosaic returns a different vocabulary — AKR1B1, CDK5, TROP2, and ten others — sourced from any indexed paper linking a target to EGFR resistance rather than from the citation-weighted canon. The edge isn't recall: it's that every bypass candidate ships with structured per-edge evidence — literature-mined resistance kinds, average extraction confidence, drugability gap score, patent and compound counts, max clinical phase, and a sourceable snippet. A pipeline-investment decision needs that scaffold; a prose answer doesn't carry it.
Mosaic
Mosaic answered by traversing the knowledge graph: find_resistance_bypass_map(target=EGFR) → 13 results; find_synthetic_lethal_whitespace(approved_target=EGFR, limit=5) → 2 results. See the tool trace for the structured evidence.
How Mosaic answered this (2 tool calls)
[
{
"tool": "find_resistance_bypass_map",
"params": {
"target": "EGFR"
},
"key_output": {
"target": "EGFR",
"indication_filter": null,
"bypass_candidates": [
{
"bypass_target": {
"symbol": "HER3",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": 0,
"compound_count": 0,
"max_clinical_phase": 0
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 2,
"resistance_kinds": [
"bypass",
"general"
],
"avg_confidence": 0.35,
"drugability_gap_score": 0.7,
"evidence_snippet": "Human epidermal growth factor receptor 3 (HER3) is a unique member of the human epidermal growth factor receptor (HER/EGFR) family, since it has negligible kinase activity. Therefore, HER3 must interact with a kinase-proficient receptor to "
},
{
"bypass_target": {
"symbol": "AKR1B1",
"name": "AKR1B1",
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 0,
"compound_count": 303,
"max_clinical_phase": 4
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 1,
"resistance_kinds": [
"acquired"
],
"avg_confidence": 0.4,
"drugability_gap_score": 0.4,
"evidence_snippet": "Acquired resistance represents a bottleneck to molecularly targeted therapies such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. A deeper understanding of resistance mechanisms can prov"
},
{
"bypass_target": {
"symbol": "HER2",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": 0,
"compound_count": 0,
"max_clinical_phase": 0
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 1,
"resistance_kinds": [
"general"
],
"avg_confidence": 0.3,
"drugability_gap_score": 0.3,
"evidence_snippet": "BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab, are valuable therapeutics for colorectal cancer (CRC), but resistance to these inhibitors is common. The reason for such resistance is not "
},
{
"bypass_target": {
"symbol": "TRANSCRIPT",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": 0,
"compound_count": 0,
"max_clinical_phase": 0
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 1,
"resistance_kinds": [
"general"
],
"avg_confidence": 0.3,
"drugability_gap_score": 0.3,
"evidence_snippet": "The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation o"
},
{
"bypass_target": {
"symbol": "CDK5",
"name": "Cyclin-dependent-like kinase 5",
"target_class": "Kinase",
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 1,
"compound_count": 352,
"max_clinical_phase": 4
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 1,
"resistance_kinds": [
"general"
],
"avg_confidence": 0.3,
"drugability_gap_score": 0.15,
"evidence_snippet": "Targeting the activated epidermal growth factor receptor (EGFR) via clustered regularly interspaced short palindromic repeat (CRISPR) technology is appealing to overcome the drug resistance of hepatocellular carcinoma (HCC) towards tyrosine"
},
{
"bypass_target": {
"symbol": "TROP2",
"name": "Tumor-associated calcium signal transducer 2",
"target_class": "Cell surface antigen",
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 100,
"compound_count": 2,
"max_clinical_phase": 4
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 2,
"resistance_kinds": [
"general"
],
"avg_confidence": 0.3,
"drugability_gap_score": 0.0059,
"evidence_snippet": "In the past 15 years, non-small cell lung cancer (NSCLC) treatment has changed with the discovery of mutations and the development of new targeted therapies and immune checkpoint inhibitors. Epidermal growth factor receptor (EGFR) was the f"
},
{
"bypass_target": {
"symbol": "SRC",
"name": "Proto-oncogene tyrosine-protein kinase Src",
"target_class": "Tyrosine kinase",
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 100,
"compound_count": 392,
"max_clinical_phase": 4
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 1,
"resistance_kinds": [
"general"
],
"avg_confidence": 0.3,
"drugability_gap_score": 0.003,
"evidence_snippet": "Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is approved as a front-line treatment for metastatic colorectal cancers, but limited efficacy is obtained. Combinatory therapy is a potentially promising stra"
},
{
"bypass_target": {
"symbol": "CA2",
"name": "Carbonic anhydrase 2",
"target_class": "Enzyme",
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 103,
"compound_count": 360,
"max_clinical_phase": 4
},
"evidence_source": "resistance_relations",
"resistance_evidence_papers": 1,
"resistance_kinds": [
"general"
],
"avg_confidence": 0.3,
"drugability_gap_score": 0.0029,
"evidence_snippet": "Drug-tolerant persister (DTP) cells are a reversible, refractory population that contributes to tumor relapse during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy in non-small cell lung cancer (NSCLC). Target"
}
],
"total": 37,
"method": "Resistance co-mentions from a deterministic keyword pass over curated literature (not GLiREL — it has no resistance edge type) + STRING PPI extended partners"
}
},
{
"tool": "find_synthetic_lethal_whitespace",
"params": {
"approved_target": "EGFR",
"limit": 5
},
"key_output": {
"anchors": [
"EGFR"
],
"lineage_filter": null,
"candidates": [
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "TP63",
"name": "Tumor protein p63",
"target_class": "Transcription factor",
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 0,
"compound_count": 50,
"validation_evidence": 93
},
"co_functionality_proxy": 0,
"co_essentiality_r": 0.3797,
"co_functionality_basis": "depmap_coessentiality",
"shared_pathways": 0,
"ppi_confidence": 0,
"coupling_strength": 0.3797,
"whitespace_score": 2.1048,
"suggested_approach": "Combination: a EGFR inhibitor + TP63 modulation; or TP63 as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "ITGB3",
"name": "ITGB3",
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 1,
"compound_count": 0,
"validation_evidence": 92
},
"co_functionality_proxy": 0.08,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 1,
"ppi_confidence": 0,
"coupling_strength": 0.08,
"whitespace_score": 0.2213,
"suggested_approach": "Combination: a EGFR inhibitor + ITGB3 modulation; or ITGB3 as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "CAV1",
"name": "caveolin 1",
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 2,
"compound_count": 0,
"validation_evidence": 0
},
"co_functionality_proxy": 0.5994,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 0,
"ppi_confidence": 0.999,
"coupling_strength": 0.5994,
"whitespace_score": 0.1998,
"suggested_approach": "Combination: a EGFR inhibitor + CAV1 modulation; or CAV1 as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "SOS2",
"name": "SOS Ras/Rho guanine nucleotide exchange factor 2",
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 4,
"compound_count": 6,
"validation_evidence": 0
},
"co_functionality_proxy": 0.5988,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 0,
"ppi_confidence": 0.998,
"coupling_strength": 0.5988,
"whitespace_score": 0.1198,
"suggested_approach": "Combination: a EGFR inhibitor + SOS2 modulation; or SOS2 as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "GABRB1",
"name": "gamma-aminobutyric acid type A receptor subunit beta1",
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": true,
"out_of_coverage": false,
"not_assessed_reason": null,
"patent_count": 0,
"compound_count": 0,
"validation_evidence": 0
},
"co_functionality_proxy": 0.08,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 1,
"ppi_confidence": 0,
"coupling_strength": 0.08,
"whitespace_score": 0.08,
"suggested_approach": "Combination: a EGFR inhibitor + GABRB1 modulation; or GABRB1 as a synthetic-lethal monotherapy in EGFR-altered tumors."
}
],
"total": 12,
"coupled_unassessed": [
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "EPGN",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": null,
"compound_count": null,
"validation_evidence": null
},
"co_functionality_proxy": 0.5994,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 0,
"ppi_confidence": 0.999,
"coupling_strength": 0.5994,
"whitespace_score": null,
"suggested_approach": "Combination: a EGFR inhibitor + EPGN modulation; or EPGN as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "DCN",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": null,
"compound_count": null,
"validation_evidence": null
},
"co_functionality_proxy": 0.5994,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 0,
"ppi_confidence": 0.999,
"coupling_strength": 0.5994,
"whitespace_score": null,
"suggested_approach": "Combination: a EGFR inhibitor + DCN modulation; or DCN as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "BTC",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": null,
"compound_count": null,
"validation_evidence": null
},
"co_functionality_proxy": 0.5994,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 0,
"ppi_confidence": 0.999,
"coupling_strength": 0.5994,
"whitespace_score": null,
"suggested_approach": "Combination: a EGFR inhibitor + BTC modulation; or BTC as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "NRG1",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": null,
"compound_count": null,
"validation_evidence": null
},
"co_functionality_proxy": 0.5994,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 0,
"ppi_confidence": 0.999,
"coupling_strength": 0.5994,
"whitespace_score": null,
"suggested_approach": "Combination: a EGFR inhibitor + NRG1 modulation; or NRG1 as a synthetic-lethal monotherapy in EGFR-altered tumors."
},
{
"anchor": {
"symbol": "EGFR",
"name": "Epidermal growth factor receptor",
"target_class": "Receptor tyrosine kinase",
"druggability_tier": null
},
"whitespace_partner": {
"symbol": "PTK2",
"name": null,
"target_class": null,
"druggability_tier": null,
"in_mosaic_kg": false,
"out_of_coverage": true,
"not_assessed_reason": "gene outside Mosaic curated coverage",
"patent_count": null,
"compound_count": null,
"validation_evidence": null
},
"co_functionality_proxy": 0.5994,
"co_essentiality_r": null,
"co_functionality_basis": "ppi_pathway_proxy",
"shared_pathways": 0,
"ppi_confidence": 0.999,
"coupling_strength": 0.5994,
"whitespace_score": null,
"suggested_approach": "Combination: a EGFR inhibitor + PTK2 modulation; or PTK2 as a synthetic-lethal monotherapy in EGFR-altered tumors."
}
],
"coupled_unassessed_total": 78,
"coverage_note": "`candidates` are partners Mosaic covers, so their patent and compound counts are measured and a whitespace claim is supportable. `coupled_unassessed` partners are outside the curated universe: their competitive status is unknown, not zero, so they carry null counts and no whitespace_score. Do not describe them as uncontested.",
"sufficient_for_absence_claim": true,
"method": "DepMap Mosaic-vs-all-genes coessentiality where available, else PPI + shared-pathway proxy",
"depmap_loaded": true,
"depmap_extended_loaded": true,
"string_extended_loaded": true,
"candidates_using_real_coessentiality": 1,
"candidates_outside_mosaic_kg": 78
}
}
]claude-sonnet-4-6 + web search
EGFR Inhibitor Resistance Targets & Development Whitespace
Well-Validated Resistance Targets (Drugged or Actively Pursued)
Off-target resistance to EGFR inhibitors (e.g., osimertinib) is driven by alternative signaling through MET amplification, HER2 amplification, HER3 upregulation, AXL overexpression, FGFR1/IGF1R dysregulation, BCL-2, CDK4/6, and MAPK/PI3K pathway reactivation.
On-target resistance includes: the T790M mutation (resistance to 1st/2nd-gen TKIs) and C797S mutation (emerging upon osimertinib treatment).
Common target-independent mechanisms also include amplification of MET and ERBB2 (HER2), as well as small cell transformation.
Preclinical data have also implicated VEGF signaling, AKT/mTOR pathway activation, and oncogenic shift to ERBB2, ERBB3, MET, or IGF-1R via overexpression or increased ligand availability.
Development Whitespace
SHP2 is an emerging resistance node: because multiple RTKs can drive osimertinib resistance, inhibiting SHP2 — a ubiquitous regulator of proximal RTK signaling — is proposed to limit RTK-dependent resistance more broadly. SHP2 inhibitors (e.g., RMC-4550) are in early clinical trials but no approved agent yet exists in this combination context.
SOS1 and SOS2 act as RAS-GEFs downstream of SHP2 and are additional RTK signaling intermediates; their inhibition may limit resistance to RTK/RAS pathway inhibitors. SOS1 inhibitors are in early-phase trials, but SOS2 remains largely undrugged.
YES1 (an SFK member) amplification is a reported resistance mechanism to osimertinib, and FAK signaling supports survival under EGFR inhibition. Selective YES1 inhibitors are not yet approved.
Nongenetic/epigenetic resistance mechanisms account for up to ~50% of escape pathways and "are usually not part of cancer panels that look for alterations in resistant patient specimens" — representing perhaps the largest whitespace overall.
CCL/CCR6 axis: A 2024 systems omics study identified CCR6 as a potential therapeutic target to overcome EGFR inhibitor resistance — currently with no dedicated clinical-stage inhibitors.
Sources: Ou et al., MedComm 2024; Sattler et al., JCM 2023; Theard et al., Mol Oncol 2024; PMC11815769 (2025); BJC 2019; PMC10972824 (2024).
gpt-4o-search-preview + web search
Resistance to epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) arises through various mechanisms, including both EGFR-dependent and EGFR-independent pathways.
EGFR-Dependent Mechanisms:
- Secondary Mutations: The T790M mutation is the most common, occurring in approximately 50–60% of cases resistant to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). (pmc.ncbi.nlm.nih.gov) The C797S mutation is a primary resistance mechanism to third-generation TKIs like osimertinib. (nature.com)
EGFR-Independent Mechanisms:
-
Activation of Alternative Signaling Pathways: Amplification of MET and HER2, as well as activation of AXL, can bypass EGFR inhibition. (molecular-cancer.biomedcentral.com)
-
Phenotypic Transformation: Transition to small-cell lung cancer (SCLC) phenotype or epithelial-mesenchymal transition (EMT) contributes to resistance. (nature.com)
Development Whitespace:
While therapies targeting EGFR-dependent mechanisms, such as fourth-generation TKIs addressing C797S mutations, are under development, (nature.com) there remains significant development whitespace in targeting EGFR-independent resistance mechanisms. Specifically, strategies to inhibit AXL activation and to reverse phenotypic transformations like EMT and SCLC transition are less explored and represent potential areas for therapeutic innovation.