Merging perspectives: genotype-directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E-cadherin–EGFR crosstalk

Clinical and Translational Medicine

Table 1 Drug sensitivities derived from in vitro models of HDGC

	CDH1 MCF10A (−/−) [13]	CDH1 MCF10A (−/−) [13]	c.1380delA CDH1 HDGC [12]	c.1380delA CDH1 HDGC [12]
	qHTS drug phenotype	Lethality by siRNA target or target ligand	qHTS drug phenotype	Target kinase in enriched top network
Drug class
PI3K inhibitor	Yes	PIK3CA, PIK3CG, PIK3R5, PIK3CB, PIK3CD, PIK3C2B	Yes	No
AKT1	No	AKT1	No	No
mTOR inhibitor	Yes		Yes	Yes
EGFR and PDGFR family inhibitor	Yes	PDGFD, EGFR, ERBB3, NRG1	No	Yes
Src kinase inhibitor	Yes		No	Yes
FAK inhibitor	?		Yes	Yes
ALK/ROS1-like tyrosine kinase inhibitor	Yes	ROS1, ALK	Yes	No
JAK family inhibitor	Yes	JAK2	No	No
BCL2 inhibitor	Yes	BCL2	No	No
Aurora kinase inhibitor	Yes		Yes	No
HDAC inhibitor	Yes	HDAC3, HDAC9, SIN3A, RERE	No
ROCK inhibitor	No		Yes	No
Protein kinase C inhibitor	No		Yes	Yes

Quantitative high-throughput drug screening of MCF10A mammary epithelial cells vs isogenic CDH1^−/− MCF10A cells and hereditary c.1380del CDH1 gastric cancer cells vs sporadic CDH1 wild type SB.msgc-1 cells. Listed are vulnerabilities selective in CDH1^−/−-mutant MCF10A and c.1380del CDH1 cells, shared drug classes are highlighted in italics
Active in both c.1380delA CDH1 mutant hereditary SB.mhdgc-1 and control CDH1 wild type SB.msgc-1 gastric cancer cells