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<MSIGDB BUILD_DATE="Jan 29, 2026" VERSION="2026.1.Hs" NAME="export">
    <GENESET STANDARD_NAME="MCCOLLUM_GELDANAMYCIN_RESISTANCE_DN" SYSTEMATIC_NAME="M14386" HISTORICAL_NAMES="" PMID="18794130" AUTHORS="McCollum AK,TenEyck CJ,Stensgard B,Morlan BW,Ballman KV,Jenkins RB,Toft DO,Erlichman C" GEOID="" EXACT_SOURCE="Table 1S: Mean Difference (log2) &lt; 0" GENESET_LISTING_URL="" EXTERNAL_DETAILS_URL="" CHIP="AFFY_HG_U133" CONTRIBUTOR="Jessica Robertson" CONTRIBUTOR_ORG="MSigDB Team" DESCRIPTION_BRIEF="Genes down-regulated in A549GARS cells (lung cancer) resistant to the geldanamycin and 17-AAG [PubChem=5476289;6440175]." DESCRIPTION_FULL="Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) and its derivative 17-allylamino-demethoxygeldanamycin (17-AAG), recent reports indicate that these inhibitors lack significant single-agent clinical activity. Resistance to Hsp90 inhibitors has been previously linked to expression of P-glycoprotein (P-gp) and the multidrug resistant (MDR) phenotype. However, the stress response induced by GA treatment can also cause resistance to Hsp90-targeted therapy. Therefore, we chose to further investigate the relative importance of P-gp and the stress response in 17-AAG resistance. Colony-forming assays revealed that high expression of P-gp could increase the 17-AAG IC(50) 6-fold in cells transfected with P-gp compared with parent cells. A549 cells selected for resistance to GA overexpressed P-gp, but verapamil did not reverse the resistance. These cells also overexpressed Hsp27, and Hsp70 was induced with 17-AAG treatment. When the GA and 17-AAG resistant cells were transfected with Hsp27 and/or Hsp70 small interfering RNA (siRNA), the 17-AAG IC(50) decreased 10-fold compared with control transfected cells. Transfection with siRNA directed against Hsp27, Hsp70, or Hsp27 and Hsp70 also increased sensitivity to EC78, a purine scaffold-based Hsp90 inhibitor that is not a P-gp substrate. We conclude that P-gp may contribute, in part, to resistance to 17-AAG, but induction of stress response proteins, such as Hsp27 and Hsp70, by Hsp90-targeted therapy plays a larger role. Taken together, our results indicate that targeting of Hsp27 and Hsp70 should be exploited to increase the clinical efficacy of Hsp90-directed therapy." TAGS="" MEMBERS="203238_s_at,206291_at,208025_s_at,215933_s_at,221526_x_at,228038_at,229768_at" MEMBERS_SYMBOLIZED="HHEX,HMGA2,NOTCH3,NTS,OR51E1,PARD3,SOX2" MEMBERS_EZID="143503,3087,4854,4922,56288,6657,8091" MEMBERS_MAPPING="203238_s_at,NOTCH3,4854|206291_at,NTS,4922|208025_s_at,HMGA2,8091|215933_s_at,HHEX,3087|221526_x_at,PARD3,56288|228038_at,SOX2,6657|229768_at,OR51E1,143503" FILTERED_BY_SIMILARITY="" FOUNDER_NAMES="" REFINEMENT_DATASETS="" VALIDATION_DATASETS="" CATEGORY_CODE="C2" ORGANISM="Homo sapiens" SUB_CATEGORY_CODE="CGP"/>
</MSIGDB>
