Reference Detail

Ref Type

Journal Article

PMID

(29496665)

Authors

Romano G, Chen PL, Song P, McQuade JL, Liang RJ, Liu M, Roh W, Duose DY, Carapeto FCL, Li J, Teh JLF, Aplin AE, Chen M, Zhang J, Lazar AJ, Davies MA, Futreal PA, Amaria RN, Zhang DY, Wargo JA, Kwong LN

Title

A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	8	5	2018 05	556-567	Cancer Discov

URL

Abstract Text

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CAE545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CAE545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CAE545K-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556-67. ©2018 AACR.See related commentary by Sullivan, p. 532See related article by Teh et al., p. 568This article is highlighted in the In This Issue feature, p. 517.

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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
NRAS Q61K PIK3CA E545K	melanoma	predicted - sensitive	Ribociclib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring NRAS Q61K and expressing PIK3CA E545K was resistant to treatment with Kisqali (ribociclib) in culture (PMID: 29496665).	29496665
NRAS G13R	melanoma	predicted - sensitive	Binimetinib + Ribociclib	Case Reports/Case Series	Actionable	In a Phase Ib/II trial, combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) resulted in a partial response lasting 119 days in a patient with melanoma harboring NRAS G13R (PMID: 29496665; NCT01781572).	29496665
NRAS Q61K PIK3CA E545K	melanoma	predicted - resistant	Binimetinib + Ribociclib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a melanoma cell line harboring NRAS Q61K and expressing PIK3CA E545K was resistant to combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) in culture and in a cell line xenograft model, demonstrating lack of tumor regression and continued tumor growth (PMID: 29496665).	29496665
NRAS Q61L PIK3CA E545K	melanoma	predicted - resistant	Ribociclib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring NRAS Q61L and expressing PIK3CA E545K was resistant to treatment with Kisqali (ribociclib) in culture (PMID: 29496665).	29496665
NRAS Q61K PIK3CA E545K	melanoma	predicted - resistant	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring NRAS Q61K and expressing PIK3CA E545K was resistant to treatment with Mektovi (binimetinib) in culture (PMID: 29496665).	29496665
NRAS Q61L PIK3CA E545K	melanoma	predicted - sensitive	Binimetinib + PF-4708671 + Ribociclib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of PF-4708671 resensitized a melanoma cell line harboring NRAS Q61L and expressing PIK3CA E545K to combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) in culture, resulting in inhibition of cell growth (PMID: 29496665).	29496665
NRAS Q61L PIK3CA E545K	melanoma	predicted - resistant	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring NRAS Q61L and expressing PIK3CA E545K was resistant to treatment with Mektovi (binimetinib) in culture (PMID: 29496665).	29496665
NRAS Q61L PIK3CA E545K	melanoma	predicted - resistant	Binimetinib + Ribociclib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring NRAS Q61L and expressing PIK3CA E545K was resistant to combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) in culture (PMID: 29496665).	29496665
NRAS Q61K PIK3CA E545K	melanoma	predicted - sensitive	Binimetinib + Ribociclib + Sirolimus	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Sirolimus (rapamycin) resensitized a melanoma cell line harboring NRAS Q61K and expressing PIK3CA E545K to combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) in culture, resulting in inhibition of cell growth (PMID: 29496665).	29496665
NRAS Q61K PIK3CA E545K	melanoma	predicted - sensitive	Binimetinib + PF-4708671 + Ribociclib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the addition of PF-4708671 resensitized a melanoma cell line harboring NRAS Q61K and expressing PIK3CA E545K to combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) in culture, resulting in inhibition of cell growth, and resulted in tumor regression and complete responses in cell line xenograft models (PMID: 29496665).	29496665
NRAS Q61L PIK3CA E545K	melanoma	predicted - sensitive	Binimetinib + Ribociclib + Sirolimus	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Sirolimus (rapamycin) resensitized a melanoma cell line harboring NRAS Q61L and expressing PIK3CA E545K to combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) in culture, resulting in inhibition of cell growth (PMID: 29496665).	29496665
NRAS Q61L	melanoma	sensitive	Binimetinib + Ribociclib	Preclinical - Cell culture	Actionable	In a preclinical study, combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) resulted in greater inhibition cell growth compared to either agent alone in a melanoma cell line harboring NRAS Q61L in culture (PMID: 29496665).	29496665
NRAS Q61K	melanoma	sensitive	Binimetinib + Ribociclib	Preclinical - Cell culture	Actionable	In a preclinical study, combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) resulted in greater inhibition cell growth compared to either agent alone in a melanoma cell line harboring NRAS Q61K in culture (PMID: 29496665).	29496665
NRAS G13R PIK3CA E545K	melanoma	predicted - resistant	Binimetinib + Ribociclib	Case Reports/Case Series	Actionable	In a Phase Ib/II trial, a patient with melanoma harboring NRAS G13R experienced disease progression on combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib), likely due to the acquisition of PIK3CA E545K (PMID: 29496665; NCT01781572).	29496665