Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation Editorial
| Authors: | Lee, M.; Morris, L. G. T. |
| Title: | Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation |
| Abstract: | A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short lived due to multiple compensatory resistance mechanisms. One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation. DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations. Copyright: © 2024 Lee and Morris. |
| Keywords: | mitogen activated protein kinase; protein kinase b; gene mutation; genetics; mutation; chemotherapy; genetic analysis; metabolism; gene expression; protein kinase inhibitor; drug resistance; cell line, tumor; phosphatidylinositol 3 kinase; histology; protein kinase inhibitors; immunotherapy; mammalian target of rapamycin; tumor cell line; guanosine triphosphatase activating protein; thyroid cancer; thyroid neoplasms; microenvironment; b raf kinase; thyroid tumor; proto-oncogene proteins b-raf; braf protein, human; scatter factor receptor; b raf kinase inhibitor; braf inhibitors; cell dedifferentiation; phosphatidylinositol 3-kinases; tor serine-threonine kinases; target of rapamycin kinase; pik3ca; protein swi; vemurafenib; genetic alteration; dabrafenib; high throughput sequencing; dna sequencing; humans; human; article; p120 gtpase activating protein; whole exome sequencing; swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 1; jak-stat signaling; anaplastic transformation; mitogen activated protein kinase kinase kinase 1; rasa1 protein, human |
| Journal Title: | Oncotarget |
| Volume: | 15 |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Date Published: | 2024-01-24 |
| Start Page: | 36 |
| End Page: | 48 |
| Language: | English |
| DOI: | 10.18632/oncotarget.28544 |
| PUBMED: | 38275291 |
| PROVIDER: | scopus |
| PMCID: | PMC10812235 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK authors: Luc GT Morris -- Source: Scopus |
