03709nas a2200889   4500000000100000008004100001260001500042100001800057700002100075700002100096700001900117700001800136700001900154700002000173700001700193700001600210700002200226700002000248700001800268700001900286700002200305700002100327700003000348700002100378700002100399700001700420700001700437700001400454700001900468700002000487700001800507700001800525700001800543700003200561700001900593700002100612700001600633700001700649700001600666700001800682700001900700700001900719700001700738700001800755700001600773700001400789700002500803700002400828700001800852700002000870700001800890700001900908700001700927700002300944700002000967700002000987700001801007700001801025700002101043700001901064700001601083700002101099700001901120700002201139700001801161700002201179700002101201700002101222700002501243700001801268700002001286245012501306856005501431300001301486490000701499520131301506       2026                            d  c2026-06-261 aHui-Hsuan Kuo1 aBhavneet Bhinder1 aHamza N. Gokozan1 aKathryn Gorski1 aPooja Chandra1 aJyothi Manohar1 aDaniela Guevara1 aJohn Otilano1 aJenna Moyer1 aMarvel Tranquille1 aSarah Ackermann1 aJared Capuano1 aCynthia Cheung1 aThomas A. Caiazza1 aPhoebe L. Reuben1 aAnastasia Murray Tsomides1 aAdriana Irizarry1 aMichael Sigouros1 aDavid Wilkes1 aAbigail King1 aTroy Kane1 aMajd Al Assaad1 aWael Al Zoughbi1 aKentaro Ohara1 aJoonghoon Auh1 aPeter Waltman1 aFlorencia P. Madorsky Rowdo1 aEnrique Podaza1 aValerie Gallegos1 aJohn Nguyen1 aRaehash Shah1 aManish Shah1 aAllyson Ocean1 aDouglas Scherr1 aNasser Altorki1 aMelissa Frey1 aAna M. Molina1 aLisa Newman1 aVivan Bea1 aEloise Chapman-Davis1 aMarcus D. Goncalves1 aAshish Saxena1 aParul J. Shukla1 aKevin Holcomb1 aRachel Simmons1 aScott Tagawa1 aJonathan H. Zippin1 aEvelyn Cantillo1 aRohit Chandwani1 aMelissa Davis1 aKelly Garrett1 aPashtoon M. Kasi1 aJennifer Marti1 aDavid Nanus1 aJones T. Nauseef1 aElizabeth Popa1 aMomin T. Siddiqui1 aAlicia Alonso1 aCora N. Sternberg1 aBishoy M. Faltas1 aOlivier Elemento1 aJuan Miguel Mosquera1 aAndrea Sboner1 aM. Laura Martin00aPatient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities  uhttps://www.science.org/doi/10.1126/sciadv.adz3351  aeadz33510 v123 aWe 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 TP53-mutant models. Our platform enables the investigation of targeted therapies and molecular drivers of drug sensitivity, providing translational insights for personalized treatment beyond current biomarker guidelines.