Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities
Hui-Hsuan Kuo, Bhavneet Bhinder, Hamza N. Gokozan, Kathryn Gorski, Pooja Chandra, Jyothi Manohar, Daniela Guevara, John Otilano, Jenna Moyer, Marvel Tranquille, Sarah Ackermann, Jared Capuano, Cynthia Cheung, Thomas A. Caiazza, Phoebe L. Reuben, Anastasia Murray Tsomides, Adriana Irizarry, Michael Sigouros, David Wilkes, Abigail King, Troy Kane, Majd Al Assaad, Wael Al Zoughbi, Kentaro Ohara, Joonghoon Auh, Peter Waltman, Florencia P. Madorsky Rowdo, Enrique Podaza, Valerie Gallegos, John Nguyen, Raehash Shah, Manish Shah, Allyson Ocean, Douglas Scherr, Nasser Altorki, Melissa Frey, Ana M. Molina, Lisa Newman, Vivan Bea, Eloise Chapman-Davis, Marcus D. Goncalves, Ashish Saxena, Parul J. Shukla, Kevin Holcomb, Rachel Simmons, Scott Tagawa, Jonathan H. Zippin, Evelyn Cantillo, Rohit Chandwani, Melissa Davis, Kelly Garrett, Pashtoon M. Kasi, Jennifer Marti, David Nanus, Jones T. Nauseef, Elizabeth Popa, Momin T. Siddiqui, Alicia Alonso, Cora N. Sternberg, Bishoy M. Faltas, Olivier Elemento, Juan Miguel Mosquera, Andrea Sboner, M. Laura Martin
We developed a pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 191 patients across 15 cancer types to advance functional precision oncology. Comprehensive characterization demonstrated high fidelity to parent tumors, with 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation. Expression profiles remained largely stable over 10 passages, ensuring reproducibility for long-term screening. Clonality analysis showed that 85% of dominant tumor clones were preserved, with genomic concordance directly reflecting clonal similarity. Even PDOs with lower concordance retained key oncogenic drivers, validating their utility as disease models. Functional assays revealed that 58% of PDOs from patients ineligible for US Food and Drug Administration–approved poly(adenosine 5′-diphosphate–ribose) polymerase inhibitors were sensitive to talazoparib, linked to DNA damage repair alterations. Furthermore, combination screens identified agents that overcome resistance, particularly in