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<p>Drug resistance of metastatic colorectal cancer (mCRC) remains a major therapeutic challenge. Screening patient-derived tumor cells with diverse compounds in 3D models may overcome the limitations of genomics-based drug response predictions. We describe a personalized functional profiling (PFP) approach in mCRC using patient-derived spheroids (PDS) and assess its utility in predicting drug responses. PDS were established from twelve patients’ tumors and validated by immunohisto(cyto)chemistry and genomic sequencing. Forty-two small molecule anti-cancer drugs, along with five standard-of-care (SOC) drugs in CRC were screened as single agents or in combination, and cell viability was measured using calcein staining or ATP-based assay. Ex vivo results were compared with clinical treatment responses. PDS closely mirrored histopathological and genetic features of the original tumors, supporting their use in PFP. Sensitivity to anti-EGFR drugs distinguished responsive from resistant patients and revealed candidates for anti-ERBB2 therapy, whereas anti-VEGFR screening failed to recapitulate clinical outcomes. SOC drug screening results correlated with clinical outcomes or tumor genetic features in a subset of PDS. This work underscores the predictive value of PFP, its complementarity with genomic sequencing, and the need for refinement to enhance its clinical applicability.</p>

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Predicting therapeutic responses in metastatic colorectal cancer through personalized functional profiling of patient-derived spheroids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Victoria El-Khoury,
  • Lejla-Nur Smajović,
  • Takouhie Mgrditchian,
  • Vanessa Barthelemy,
  • Pauline Torigny,
  • Hichul Kim,
  • Jean-Jacques Gerardy,
  • Petr V. Nazarov,
  • Jérôme Graas,
  • Myriam Menster,
  • Katrin B. M. Frauenknecht,
  • Bob Edon,
  • Boris Meuter,
  • Bernard Faber,
  • Jan Friedrich Krahn,
  • Samer Abi-Khalil,
  • Barbara Klink,
  • Daniel Stieber,
  • Felix Bruno Kleine Borgmann,
  • Guy Berchem,
  • Michel Mittelbronn,
  • Marc Berna,
  • Yong-Jun Kwon

摘要

Drug resistance of metastatic colorectal cancer (mCRC) remains a major therapeutic challenge. Screening patient-derived tumor cells with diverse compounds in 3D models may overcome the limitations of genomics-based drug response predictions. We describe a personalized functional profiling (PFP) approach in mCRC using patient-derived spheroids (PDS) and assess its utility in predicting drug responses. PDS were established from twelve patients’ tumors and validated by immunohisto(cyto)chemistry and genomic sequencing. Forty-two small molecule anti-cancer drugs, along with five standard-of-care (SOC) drugs in CRC were screened as single agents or in combination, and cell viability was measured using calcein staining or ATP-based assay. Ex vivo results were compared with clinical treatment responses. PDS closely mirrored histopathological and genetic features of the original tumors, supporting their use in PFP. Sensitivity to anti-EGFR drugs distinguished responsive from resistant patients and revealed candidates for anti-ERBB2 therapy, whereas anti-VEGFR screening failed to recapitulate clinical outcomes. SOC drug screening results correlated with clinical outcomes or tumor genetic features in a subset of PDS. This work underscores the predictive value of PFP, its complementarity with genomic sequencing, and the need for refinement to enhance its clinical applicability.