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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 Cancer discovery
Vol 8
Issue 5
Date 2018 05
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 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 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 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 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 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 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 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 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 + 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 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
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 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