Table 2.
Genomic alterations and examples of potential targeted (either on- or off- label) therapeutic.
| Gene Alteration | Gene Function | Examples of Potential on/off-Label Therapy | Examples of Potential Experimental Therapy/Clinical Trial * | Ref. |
|---|---|---|---|---|
| ABL1/2 | ABL (Abelson tyrosine-protein) kinase regulates cell survival and division/differentiation | Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib | ||
| APC | APC (adenomatous polyposis coli) is a tumor suppressor, regulating cell division/adhesion, controls Wnt signaling pathway | Sulindac (Tankyrase inh) | [13] | |
| ARID1A | ARID1A (AT-rich interactive domain-containing protein 1A) regulates transcription | Dasatinib, EZH2 inh. | Talazoparib Tosylate NCT02286687 ** | |
| ASXL1 | ASXL1 (additional sex combs-like1) regulates transcription and ubiquitin-proteasome protein degradation via BAP pathway. | Cabozantinib | [14] | |
| ATM | ATM (ataxia telangiectasia mutated) regulates DNA damage response via the PI3K-like protein kinase pathway | Olaparib | [15] | |
| BCL2 | BCL2 (B-cell lymphoma 2) regulates apoptosis | Venetoclax | [16] | |
| BRAF | BRAF regulates cell growth via MAPK (RAF-MEK-ERK) signaling cascade | Dabrafenib, Regorafenib, Trametinib, Vemurafenib, Cobimetinib | [17] | |
| BRCA2 | BRCA2 (breast cancer 1/2) regulates DNA double-strand break repair | Olaparib, Niraparib, Rucaparib | ||
| BRIP1 | BRIP1 (BRCA1-interacting protein 1) functions in DNA repair | Olaparib | ||
| BTK | BTK (Bruton’s tyrosine kinase) regulates B-cell receptor signaling and B-cell development | Ibrutinib, Acalabrutinib | [18] | |
| CCND2 | CCND1/3 (cyclin D1/3) regulates cell cycle via CDK4/6 | Palbociclib | [19] | |
| CD274 | CD274 (cluster of differentiation 274) encodes immune inhibitory receptor B7-H1, also known as programmed cell death ligand-1 (PD-L1) | Atezolizumab, Avelumab, Durvalumab, Nivolumab, Pembrolizumab | ||
| CD79B | CD79A/B (cluster of differentiation 79) complexes with B-cell receptor, mediates downstream signaling to the NF-kB, PI3K, MAPK and NF-AT pathways | Ibrutinib | Polatuzumab vedotin | [20] |
| CDK4 | CDK4 (cyclin-dependent kinase 4) regulates cell cycle | Palbociclib, Ribociclib | [19] | |
| CDKN2A/B | CDKN2A (cyclin dependent kinase inhibitor encodes tumor suppressors and regulates cell cycle; loss results in increased CDK4/6 | Palbociclib, Ribociclib | [19] | |
| CSF1R | CSF1 (colony stimulating factor 1) regulates differentiation and survival | Chiauranib NCT03074825 ** | ||
| CXCR4 | CXCR4 (C-X-C chemokine receptor type 4) regulates hematopoiesis and CD20 expression | Plerixafor | BMS-936564 NCT01120457 ** | [21] |
| DNMT3A | DNMT3A (DNA methyltransferase 3A) regulates gene expression | Azacitidine, Decitabine | [22] | |
| EP300 | Histone acetyltransferase p300 regulates transcription via chromatin remodeling | Mocetinostat NCT02282358 ** | ||
| ERBB4 | Member of the EGFR (epidermal growth factor receptor) regulates proliferation | Trastuzumab, Pertuzumab Afatinib, Erlotinib, Lapatinib | ||
| EZH2 | EZH2 (enhancer of zeste-homolog 2) regulates DNA methylation and transcription repression | Tazemetostat (NCT02601950) ** | [23] | |
| FGFR3 | FGFR3 (fibroblast growth factor receptor 3) promotes cell cycle via activation of RAS/MAPK/AKT pathway | Lenvatinib, Pazopanib, Ponatinib, Regorafenib | ||
| FLT3 | FLT3 (FMS-like tyrosine kinase 3) activates signaling of Akt1, RAS, ERK, and mTOR. | Midostaurin, Gilteritinib Quizartinib | [9,24] | |
| FLT4 | FLT4 (FMS like tyrosine kinase 4), also known as VEGFR-3 (vascular endothelial growth factor receptor 3) | Sorafenib, Sunitinib, Pazopanib, Axitinib, Vandetanib, | [25] | |
| GNAS | GNAS (Guanine nucleotide binding protein, α stimulating) regulates adenylate cyclase via MAPK | Trametinib | ||
| IDH1 | IDH1 (isocitrate dehydrogenases 1) | Azacitidine, Decitabine | [26] | |
| IDH/2 | IDH2 (isocitrate dehydrogenases 2) regulates citric acid (Krebs) cycle and cell metabolism | Enasidenib | [27] | |
| IGF1R | IGF1R (insulin-like growth factor-1 receptor) mediates anti-apoptotic signals | Ganitumab NCT00562380 ** | ||
| JAK1 | JAK1 (Janus kinase 1) in involved in signal regulation | Tofacitinib | Fedratinib | [28] |
| JAK2 | JAK2 (Janus kinase 2) is involved in signal regulation | Ruxolitinib | [29] | |
| KIT | KIT (also known as c-Kit or CD117), activates PI3K/Akt and RAS/MAPK signaling pathway | Imatinib, Midastaurin | ||
| KRAS | KRAS (Kirsten rat sarcoma) regulates signal transduction via MAPK pathway | Cetuximab, Trametinib, Panitumumab, Regorafenib | [30] | |
| MAP2K1 | MAP2K1 (mitogen-activated protein kinase 1 (MKK1 or MEK1) mediates RAS/RAF/MAPK pathway | Cobimetinib, Selumetinib, Trametinib | ||
| MAP3K14 | MAP3K14 (mitogen-activated protein kinase 14) also known as NF-kappa-B-inducing kinase | Trametinib | ||
| MLL | MLL (mixed lineage leukemia) encodes a histone methyltransferase | EPZ-5676 NCT02141828 ** | ||
| MSH2 | MSH2 (MutS homolog2) is a tumor suppressor encodes DNA mismatch repair (MMR) protein 2 | Atezolizumab, Nivolumab Pembrolizumab | ||
| MSH6 | MSH6 (MutS homolog 6) encodes DNA mismatch repair (MMR) protein 6 involved in DNA repair | Atezolizumab, Nivolumab Pembrolizumab | ||
| MYC | MYC regulates cell cycle progression, apoptosis, proliferation | BET inhibitors NCT02431260 ** | ||
| MYD88 | MYD88 (myeloid differentiation primary response gene 88) activates transcription factor NFkB | Ibrutinib, acalabrutinib (IRAK1 inh) | zanubrutinib | [7] |
| NF1/2 | NF1 (neurofibromin 1/2) a GTPase-activating negative regulator of the RAS signaling pathway | Everolimus, Temsirolimus, Trametinib | ||
| NRAS | NRAS (neuroblastoma RAS) mediates signal transduction via RAF/MEK/ERK and PI3K | Trametinib, Panitumumab | [31] | |
| PALB2 | PALB2 (partner and localizer of BRCA2) | Olaparib | [32] | |
| PDCD1LG2 | Programmed cell death 1 ligand 2 (also known as CD273) essential for T-cell proliferation | Atezolizumab, Avelumab, Durvalumab, Nivolumab, Pembrolizumab | ||
| PIK3CA | PIK3CA (phosphatidylinositol 3-kinase (PI3K), which regulates the PI3K/AKT/MTOR axis | Everolimus, Temsirolimus, Copanlisib, Duvalisib, Idelalisib | Taselisib NCT02465060 ** | |
| PIK3R1 | PIK3R1 (PI3K regulatory subunit alpha) | Copanlisib | NCT02369016 ** | |
| PTCH1 | PTCH1 (Protein patched homolog 1) is a receptor for Sonic hedgehog (Shh) for gene transcription | Vismodegib, Sonidegib | [33] | |
| PTEN | PTEN (phosphatase and tensin homolog) is a tumor suppressor, functions via PI3K/AKT/mTOR pathway | Everolimus, Temsirolimus | [34] | |
| PTPN11 | PTPN11 (Tyrosine-protein phosphatase non-receptor type 11) activates PI3K, MEK axis | Trametinib, | [35] | |
| RET | RET (rearranged during transfection) is a proto-oncogene | Cabozantinib, Sorafenib, Vandetanib, Lenvatinib | [36] | |
| RUNX1 | RUNX1 (Runt-related transcription factor, also known as acute myeloid leukemia 1 protein (AML1), core-binding factor subunit alpha 2 (CBFA2) is a tumor suppressor | Mocetinostat (MGCD0103) or Sorafenib NCT00217646 ** | ||
| STAT3 | STAT3 (signal transducer and activator of transcription 3) encodes a transcription factor | AZD9150 (NCT01839604) ** | ||
| STK11 | STK11 (serine/threonine kinase 11) functions as a tumor suppressor gene | Dasatinib, Bosutinib, Everolimus, Temsirolimus | ||
| TET2 | TET2 (Tet methylcytosine dioxygenase 2) regulates DNA demethylation | Azacitidine, Decitabine | [37] | |
| TP53 | TP53 (Tumor protein p53) is a tumor suppressor; loss leads to overexpression of VEGF levels | Bevacizumab, Pazopanib | Wee-1 inh, MDM inh, PRIMA-1MET inhibitors. | [38] |
| VHL | VHL (von Hippel-Lindau) is a tumor suppressor activates the HIF/VEGF pathway | Axitinib, Bevacizumab, Everolimus, Pazopanib, Sorafenib, Sunitinib, Temsirolimus, Vandetanib, | ||
| XPO1 | XPO1 (exportin-1) regulates nuclear export of tumor suppressor genes | Selinexor NCT02227251 |
* Experimental drugs in clinical trials are generally only mentioned if there are no FDA-approved drugs that impact that target. ** Numbers refer to clinicaltrials.gov identifier (https://clinicaltrials.gov/ct2/show).