Reference Detail

Ref Type

Journal Article

PMID

(27798265)

Authors

Zhang L, Theodoropoulos PC, Eskiocak U, Wang W, Moon YA, Posner B, Williams NS, Wright WE, Kim SB, Nijhawan D, De Brabander JK, Shay JW

Title

Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	8	361	2016 Oct 19	361ra140	Sci Transl Med

URL

Abstract Text

Mutations in the adenomatous polyposis coli (APC) gene are common in colorectal cancer (CRC), and more than 90% of those mutations generate stable truncated gene products. We describe a chemical screen using normal human colonic epithelial cells (HCECs) and a series of oncogenically progressed HCECs containing a truncated APC protein. With this screen, we identified a small molecule, TASIN-1 (truncated APC selective inhibitor-1), that specifically kills cells with APC truncations but spares normal and cancer cells with wild-type APC. TASIN-1 exerts its cytotoxic effects through inhibition of cholesterol biosynthesis. In vivo administration of TASIN-1 inhibits tumor growth of CRC cells with truncated APC but not APC wild-type CRC cells in xenograft models and in a genetically engineered CRC mouse model with minimal toxicity. TASIN-1 represents a potential therapeutic strategy for prevention and intervention in CRC with mutant APC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TASIN-1	TASIN-1	8	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TASIN-1				TASIN-1 is a small molecule that selectively inhibits growth of cancer cells expressing truncated APC through inhibition of cholesterol biosynthesis (PMID: 27798265, PMID: 31070915).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
APC wild-type	colorectal cancer	resistant	TASIN-1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, TASIN-1 did not inhibit survival of APC wild-type colorectal cancer cells in culture or in cell line xenograft models (PMID: 27798265).	27798265
APC L1488*	colorectal cancer	sensitive	TASIN-1	Preclinical - Cell culture	Actionable	In a preclinical study, TASIN-1 inhibited survival of colorectal cancer cells harboring APC L1488* in culture (PMID: 27798265).	27798265
APC inact mut	colorectal cancer	sensitive	TASIN-1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, TASIN-1 efficiently inhibited survival of colorectal cancer cell lines harboring APC truncation mutations in culture and in cell line xenograft models (PMID: 27798265).	27798265
APC E853* APC K1555*	colorectal cancer	sensitive	TASIN-1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, TASIN-1 efficiently inhibited survival of colorectal cancer cells harboring APC E853* and APC K1555* in culture and inhibited tumor growth in xenograft models (PMID: 27798265).	27798265
APC Q1131* APC Q1303*	colorectal cancer	sensitive	TASIN-1	Preclinical - Cell culture	Actionable	In a preclinical study, TASIN-1 inhibited survival of colorectal cancer cells harboring APC Q1131* and APC Q1303* in culture (PMID: 27798265).	27798265
APC Q1338*	colorectal cancer	sensitive	TASIN-1	Preclinical - Cell culture	Actionable	In a preclinical study, TASIN-1 inhibited survival of colorectal cancer cell lines harboring APC Q1338* in culture (PMID: 27798265).	27798265
APC E1309*	colorectal cancer	sensitive	TASIN-1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, TASIN-1 efficiently inhibited survival of colorectal cancer cells harboring APC E1309* in culture and in cell line xenograft models (PMID: 27798265).	27798265
APC G1416*	colorectal cancer	sensitive	TASIN-1	Preclinical - Cell culture	Actionable	In a preclinical study, TASIN-1 inhibited survival of colorectal cancer cell lines harboring APC G1416* in culture (PMID: 27798265).	27798265