Fig 2: a–d Density distributions of the CDH1-/-/MCF10A viability ratios for non-sensory GPCRs, orphan GPCRs, taste GPCRs and G proteins. e–g Density distributions of the CDH1-/-/MCF10A viability ratios for signalling pathways associated with intact adherens junctions: PI3K/AKT, WNT pathway and HIPPO pathway. Pathway genes were obtained from KEGG. The statistical significance was determined using the Kolmogorov–Smirnov test. h Boxplot of the functional subgroups in the PI3K/AKT pathway. Note that all subgroups with the exception of the phosphatases are shifted in the synthetic lethal direction (viability ratio < 1). i–j Normalised cell counts 48 h after treatment with serial dilutions of AZD5363 and PI103. For each drug, both the MCF10A and NCI-N87 isogenic pair are shown (wild-type black bars; CDH1-/- grey bars). Six fields/well at 4× magnification were captured using the Cytation 5 imager (Biotek). Nuclei were counted using Gen5 (Biotek) and normalised to the vehicle control for each cell line

Fig 3: Gastric cancer cells lacking E-cadherin have enhanced sensitivity to the allosteric AKT inhibitors ARQ092 and MK2206. (A) Western blots of pAKT-Ser473, pan-AKT, and ß-actin in NCI-N87-WT and CDH1-/- cells. (B) Relative expression of pAKT and pan-AKT in NCI-N87-WT and CDH1-/- cells. (C–F) Normalised NCI-N87-WT and CDH1-/- cell counts 48 h after treatment with serial dilutions of ARQ-092 (C), MK2206 (D), perifosine (E), and SC66 (F). Wild-type, black bars; CDH1-/-, grey bars. Six fields per well at 4× magnification were captured using the Cytation 5 imager (Biotek). Nuclei were counted using Gen5 (Biotek, Winooski, Vermont) and normalised to the vehicle control for each cell line. (For all graphs, error bars = SEM; ns = p > 0.05, * = p < 0.05, ** = p < 0.01, n = 3 independent biological replicates; unpaired two-sided t-test.)

Fig 4: NEDDylation regulates cell sensitivity to H 2 O 2 -induced oxidative stress. (A and B) Analysis of the effect of NEDP1 deletion (A) or UBC12 deletion on cell sensitivity in response to H2O2 treatment. In (A and B), HEK293T WT, Nedp1 -/- or Ubc12 -/- cells were cultured in 96-well plates. After 24 h, cells were treated with H2O2 at indicated dose for 1 h, and then incubated with CCK8 for 4 h. OD450 was measured using BioTek Cytation 5, triplicates were performed. Results are provided as mean ± SD. (C and D) Analysis of the effect of UBC12 deletion on cell sensitivity in response to cisplatin (C) or HU (D) treatment. In (C and D), HEK293T WT or Ubc12 -/- cells were cultured and cell cytotoxicity assay was performed as described above

Fig 5: E-cadherin-deficient gastric organoids are more sensitive to pan-HDAC inhibitors. WT, Cdh1-/- and Cdh1-/-/Tp53-/- organoids were drugged for 48 h with the different pan-HDAC inhibitors, and the area of the organoids was then measured and normalized to their respective vehicle controls. RFP fluorescence was used to detect tdTomato and determine the area of the organoids, using Cytation 5 imager (Biotek, Winooski, VT, USA). (A) Entinostat induced a synthetic lethal effect with a maximum of 44% differences between WT organoids and Cdh1-/- ones and 40% for the Cdh1-/-/Tp53-/- organoids. (B) Pracinostat induced an SL effect up to 40% and 20% for the Cdh1-/- and the Cdh1-/-/Tp53-/- organoids respectively. (C) Mocetinostat preferentially targeted E-cadherin-deficient cells with a maximum of 39% decrease in Cdh1-/- area compared to WT ones and had no effect for Cdh1-/-/Tp53-/- organoids. (D) Vorinostat did not present any significant synthetic lethal effect between the WT and the E-cadherin-deficient gastric organoids. n = 3–5 per compound. All the IC50 are summarized in Table S5. Statistically significant results are labeled as * p < 0.05, ** p < 0.01 and *** p < 0.001. (E) Picture representation of WT, Cdh1-/- and Cdh1-/-/Trp53-/- organoids after 7.5 µM entinostat, 0.25 µM pracinostat, 0.63 µM mocetinostat and 0.63 µM vorinostat.