Reference Detail

Ref Type

Journal Article

PMID

(27974663)

Authors

Anderson GR, Wardell SE, Cakir M, Crawford L, Leeds JC, Nussbaum DP, Shankar PS, Soderquist RS, Stein EM, Tingley JP, Winter PS, Zieser-Misenheimer EK, Alley HM, Yllanes A, Haney V, Blackwell KL, McCall SJ, McDonnell DP, Wood KC

Title

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	8	369	2016 Dec 14	369ra175	Sci Transl Med

URL

Abstract Text

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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
PIK3CA act mut	breast cancer	predicted - sensitive	Torin 1 + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Torin1 sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA E545K	breast cancer	predicted - sensitive	Dactolisib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 sensitized breast cancer cell lines harboring PIK3CA E545K to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA act mut	breast cancer	no benefit	Alpelisib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, Alpelisib (BYL719) did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663).	27974663
BRAF act mut	colorectal cancer	predicted - sensitive	VX-11e + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Erk signaling by VX-11e sensitized colorectal cancer cell lines harboring KRAS or BRAF activating mutations to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA act mut	breast cancer	predicted - sensitive	Vistusertib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Vistusertib (AZD2014) sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA act mut	breast cancer	no benefit	Buparlisib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, Buparlisib (BKM120) did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA wild-type	breast cancer	predicted - sensitive	A-1210477 + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, combination of WEHI-539 and A-1210477 resulted in enhanced apoptosis in PIK3CA wild-type breast cancer cell lines in culture (PMID: 27974663).	27974663
PIK3CA H1047R PTEN loss	breast cancer	predicted - sensitive	Dactolisib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 sensitized breast cancer cell lines harboring PIK3CA H1047R and PTEN loss to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA H1047R PTEN loss	breast cancer	no benefit	Dactolisib + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 did not sensitize breast cancer cell lines harboring PIK3CA H1047R and PTEN loss to Venclexta (venetoclax) in culture (PMID: 27974663).	27974663
PIK3CA E545K	breast cancer	no benefit	Dactolisib + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 did not sensitize breast cancer cell lines harboring PIK3CA E545K to Venclexta (venetoclax) in culture (PMID: 27974663).	27974663
PIK3CA act mut	breast cancer	predicted - sensitive	Dactolisib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA H1047R PTEN loss	triple-receptor negative breast cancer	predicted - sensitive	ABT-737 + Sapanisertib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ABT-737 and Sapanisertib (MLN0128) combination treatment resulted in inhibition of tumor growth in cell line xenograft models of triple-receptor negative breast cancer harboring PIK3CA H1047R and PTEN loss (PMID: 27974663).	27974663
PIK3CA wild-type	breast cancer	no benefit	Dactolisib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 did not sensitize PIK3CA wild-type breast cancer cell lines to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA act mut	breast cancer	predicted - sensitive	Sapanisertib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Sapanisertib (MLN0128) sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA E542K PTEN loss	breast cancer	predicted - sensitive	Dactolisib + WEHI-539	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 sensitized breast cancer cell lines harboring PIK3CA E542K and PTEN loss to WEHI-539 in culture (PMID: 27974663).	27974663
PIK3CA H1047R PTEN loss	triple-receptor negative breast cancer	predicted - sensitive	ABT-737 + Dactolisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ABT-737 and BEZ235 combination treatment resulted in tumor regression in cell line xenograft models of triple-receptor negative breast cancer harboring PIK3CA H1047R and PTEN loss (PMID: 27974663).	27974663
BRAF act mut	colorectal cancer	no benefit	Venetoclax + VX-11e	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Erk signaling by VX-11e did not sensitize colorectal cancer cell lines harboring KRAS or BRAF activating mutations to Venclexta (venetoclax) in culture (PMID: 27974663).	27974663
PIK3CA act mut	breast cancer	no benefit	Dactolisib + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, inhibition of Pi3k signaling by BEZ235 did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to Venclexta (venetoclax) in culture (PMID: 27974663).	27974663