Integration of genomic sequencing drives therapeutic targeting of PDGFRA in T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma Journal Article
| Authors: | Paolino, J.; Dimitrov, B.; Apsel Winger, B.; Sandoval-Perez, A.; Rangarajan, A. V.; Ocasio-Martinez, N.; Tsai, H. K.; Li, Y.; Robichaud, A. L.; Khalid, D.; Hatton, C.; Gillani, R.; Polonen, P.; Dilig, A.; Gotti, G.; Kavanagh, J.; Adhav, A. A.; Gow, S.; Tsai, J.; Li, Y.; Ebert, B. L.; Van Allen, E. M.; Bledsoe, J.; Kim, A. S.; Tasian, S. K.; Cooper, S. L.; Cooper, T. M.; Hijiya, N.; Sulis, M. L.; Shukla, N. N.; Magee, J. A.; Mullighan, C. G.; Burke, M. J.; Luskin, M. R.; Mar, B. G.; Jacobson, M. P.; Harris, M. H.; Stegmaier, K.; Place, A. E.; Pikman, Y. |
| Article Title: | Integration of genomic sequencing drives therapeutic targeting of PDGFRA in T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma |
| Abstract: | PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. EXPERIMENTAL DESIGN: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. RESULTS: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. CONCLUSIONS: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making. ©2023 American Association for Cancer Research. |
| Keywords: | child; genetics; mutation; t lymphocyte; t-lymphocytes; mouse; animal; animals; mice; platelet derived growth factor alpha receptor; receptor, platelet-derived growth factor alpha; protein tyrosine kinase; acute lymphoblastic leukemia; precursor cell lymphoblastic leukemia-lymphoma; receptor protein-tyrosine kinases; precursor t-cell lymphoblastic leukemia-lymphoma; humans; human |
| Journal Title: | Clinical Cancer Research |
| Volume: | 29 |
| Issue: | 22 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-11-15 |
| Start Page: | 4613 |
| End Page: | 4626 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-2562 |
| PUBMED: | 37725576 |
| PROVIDER: | scopus |
| PMCID: | PMC10872648 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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