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We present a patient with an IMT who initially responded to first-line alectinib, but who later suffered disease relapse and presently survives with moderate residual disease after receiving second-line lorlatinib. Biopsy specimens were analyzed using next generation sequencing (DNA-seq and RNA-seq) and reverse phase protein microarray (RPPA) as part of an institutional Molecular Tumor Board (MTB) study. An EML4-ALK rearrangement and EGFR activation (pEGFRY1068) were present in both the primary and recurrent tumors, while a secondary ALK I1171N mutation was exclusive to the latter. EGFR signaling in the background of a secondary ALK mutation is correlated with reduced ALK TKI sensitivity in vitro, implicating an important mechanism of drug resistance development in this patient. The RPPA results also critically demonstrate that ALK signaling (ALKY1604) was not activated in the recurrent tumor, thereby indicating that standard-of-care use of third- or fourth-line ALK TKI would not likely be efficacious or durable. These results underscore the importance of real-time clinical integration of functional protein drug target activation data with NGS in the MTB setting for improving selection of patient-tailored therapy.<\/jats:p>","DOI":"10.1093\/oncolo\/oyad129","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T18:03:42Z","timestamp":1685037822000},"page":"730-736","source":"Crossref","is-referenced-by-count":16,"title":["Integration of Multi-omic Data in a Molecular Tumor Board Reveals EGFR-Associated ALK-Inhibitor Resistance in a Patient With Inflammatory Myofibroblastic Cancer"],"prefix":"10.1093","volume":"28","author":[{"given":"Allison L","family":"Hunt","sequence":"first","affiliation":[{"name":"Women\u2019s Health Integrated Research Center, Women\u2019s Service Line, Inova Health System , Annandale, VA , USA"},{"name":"Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center , Bethesda, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aratara","family":"Nutcharoen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Inova Fairfax Hospital , Falls Church, VA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Randall","sequence":"additional","affiliation":[{"name":"Inova Schar Cancer Institute, Inova Health System , Fairfax, VA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Papazian","sequence":"additional","affiliation":[{"name":"Inova Schar Cancer Institute, Inova Health System , Fairfax, VA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Deeken","sequence":"additional","affiliation":[{"name":"Inova Schar Cancer Institute, Inova Health System , Fairfax, VA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G Larry","family":"Maxwell","sequence":"additional","affiliation":[{"name":"Women\u2019s Health Integrated Research Center, Women\u2019s Service Line, Inova Health System , Annandale, VA , USA"},{"name":"Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center , Bethesda, MD , USA"},{"name":"The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University , Bethesda, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W","family":"Bateman","sequence":"additional","affiliation":[{"name":"Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center , Bethesda, MD , USA"},{"name":"The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University , Bethesda, MD , USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. , Bethesda, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuel F","family":"Petricoin","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine, George Mason University , Manassas, VA , USA"},{"name":"Theralink Technologies, Inc. , Golden, CO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Benyounes","sequence":"additional","affiliation":[{"name":"Inova Schar Cancer Institute, Inova Health System , Fairfax, VA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4742-3281","authenticated-orcid":false,"given":"Thomas P","family":"Conrads","sequence":"additional","affiliation":[{"name":"Women\u2019s Health Integrated Research Center, Women\u2019s Service Line, Inova Health System , Annandale, VA , USA"},{"name":"Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center , Bethesda, MD , USA"},{"name":"The John P. 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