Fig. 7: p53-mutant murine organoids and human PDOs synergistically reduce their viability after combined CDK4/6 and HSP90 inhibition.
A Cell viability matrix of p53-mutant (mutp53) murine CRC tumor organoids treated with Ganetespib and Palbociclib alone or in combination for 72 h. Organoids were generated from AOM/DSS-treated TP53R248Q mutant mice [39]. n = 3 biological replicates (different passages) with 3 in-plate technical replicates each were measured. B Cell viability matrices of TP53 mutant (mutp53) patient-derived organoids (PDOs) from 2 different patients (PDO #3 and PDO #4) treated with Ganetespib, Palbociclib alone or in combination for 72 h (left) and 96 h (right). PDOs were cultivated and treated as small organoids. C Cell viability matrix of mutp53-containing PDO #3 treated with Ganetespib, Palbociclib alone or in combination for 48 h or 72 h. PDOs were cultivated and treated as large organoids. n = 5 biological replicates (different passages) with 3 in-plate technical replicates each were measured. D Cell viability matrices of a mutp53-haboring matched PDO pair (chemo-responsive and chemo-resistant) from one patient treated with Ganetespib and Palbociclib alone or in combination for 96 h. Both PDOs were cultivated and treated as small organoids. A–D Color scheme represents changes in cell viability. Numbers in the matrix are HSA synergy scores. Synergy scores: <−10 antagonistic; −10 to 10 additive; >10 synergistic. For each PDO culture n ≥ 2 replicates (different passages) with ≥2 in-plate technical replicates each were measured. Bottom, Representative brightfield images of organoids after the indicated treatments. Scale bars, 200 μm.
