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|Ref Type||Journal Article|
|Authors||Hunt AL, Nutcharoen A, Randall J, Papazian A, Deeken J, Maxwell GL, Bateman NW, Petricoin EF, Benyounes A, Conrads TP, Cannon TL|
|Title||Integration of Multi-omic Data in a Molecular Tumor Board Reveals EGFR-Associated ALK-Inhibitor Resistance in a Patient With Inflammatory Myofibroblastic Cancer.|
|Abstract Text||Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade mesenchymal neoplasms commonly characterized by chromosomal rearrangements causing constitutive activation of anaplastic lymphoma kinase (ALK) and/or ALK mutations causing reduced sensitivity to ALK tyrosine kinase inhibitors (TKI). 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.|
|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|
|EML4 - ALK ALK I1171N||inflammatory myofibroblastic tumor||predicted - resistant||Alectinib||Case Reports/Case Series||Actionable||In a clinical case study, ALK I1171N was identified on post-progression biopsy in a patient with inflammatory myofibroblastic tumor of the lung harboring EML4-ALK, who previously responded to Alecensa (alectinib) (PMID: 37255276).||37255276|
|EML4 - ALK ALK I1171N||inflammatory myofibroblastic tumor||predicted - sensitive||Lorlatinib||Case Reports/Case Series||Actionable||In a clinical case study, Lorbrena (lorlatinib) treatment resulted in near resolution of the pleural effusion and decrease in pleural mass in a patient with inflammatory myofibroblastic tumor of the lung harboring EML4-ALK and ALK I1171N (PMID: 37255276).||37255276|
|EML4 - ALK||inflammatory myofibroblastic tumor||predicted - sensitive||Alectinib||Case Reports/Case Series||Actionable||In a clinical case study, Alecensa (alectinib) treatment resulted in a near-complete radiographic response after 3 months in a patient with inflammatory myofibroblastic tumor of the lung harboring EML4-ALK (PMID: 37255276).||37255276|