Author(s): Michael GMccuskerJr. , Katherine A. Scilla and ChristianRolfo
The unprecedented understand ing of molecular alterations driving tumorigenesis in the genomic era has led to a shift away from the use of cytotoxic chemotherapy designed to indiscriminately destroy rapidly dividing cells to a more precise approach of targeting cancer cells based on specific molecular alterations in tumor DNA. Targeted therapy preferentially damages malignant cells while sparing normal cells by blocking the action of mutated enzymes, proteins, or molecules that perpetuate or “drive” growth and survival of cancer cells. Several of these therapies directly target mutated tyrosine kinases. Tyrosine kinases are enzymes that catalyze the transfer of a phosphate group from adenosine triphosphate (ATP) to a protein within a cell, switching the cell from a state of inactivation to activation. Enzyme-specific drugs target constitutively active mutated tyrosine kinases generated by somatic DNA alterations, while nonspecific “multikinase” inhibitors target several enzymes that are upregulated in cancer cells and are involved in cell survival, angiogenesis, and metastasis. Other targeted agents affect novel proteins and enzymes involved in the process of tumorigenesis. The goal of this chapter is to describe frequently used targeted therapies, affected enzymatic pathways, and common clinical applications.
There are four members of the ErbB or human epidermal growth factor receptor (HER) family of receptors. All members have tyrosine kinase domains (TKDs) on the cytoplasmic side of the cell membrane. Binding of ligand s to HER induces homodimerization or heterodimerization of the receptors. Dimerization results in phosphorylation of the TKDs and induces several intracellular signaling cascades. This leads to cellular survival, proliferation, and angiogenesis. Epidermal growth factor receptor (EGFR) is also known as ErbB1 or HER1. EGFR mutations negate the need for ligand binding and lead to autophosphorylation of TKDs (Figure 11.1).
In the treatment of EGFR-mutated advanced non–small-cell lung cancer (NSCLC), the first-generation EGFR tyrosine kinase inhibitor (TKI), erlotinib, was found to significantly prolong progression-free survival (PFS) compared to platinum doublet chemotherapy. Data from 13 phase 3 trials of patients treated with EGFR TKI or platinum-based chemotherapy were described in a meta-analysis from 2,620 patients (1,475 with and 1,145 without EGFR mutation). In patients with EGFR mutation, EGFR TKI was associated with a significantly decreased risk of disease progression in the front-line or subsequent treatments.1 EGFR-mutated NSCLC can develop resistance mutations that allow escape from tyrosine kinase inhibition during treatment with first- and second-generation EGFR TKIs.2
Osimertinib is a third-generation EGFR TKI that was designed to overcome the most common acquired resistance mechanism, T790M. In advanced EGFR-mutated NSCLC, osimertinib demonstrated improved PFS when compared to first-generation EGFR TKI therapy (erlotinib or gefitinib) in the first-line setting.3 Osimertinib was shown to have improved intracranial penetration when compared to earlier generation TKIs and is now used in the first-line setting for metastatic NSCLC with intracranial metastasis.4
Lapatinib and neratinib are dual EGFR and HER2 TKIs approved for use in HER2-overexpressed breast cancer.5–7
VEGFs are signaling proteins for VEGF receptors and are important for angiogenesis (Figure 11.2). VEGF receptor dimerization induces intracellular signaling cascades, and VEGF receptor mutations negate the need for ligand binding to active tyrosine kinase domains. VEGF receptor mutations are found in several solid tumor malignancies including colon cancer, gastric cancer, kidney cancer, liver cancer, sarcoma, and thyroid cancer. Small molecule VEGF inhibitors are mostly multikinase inhibitors. Serious adverse effects of these medications include those related to blood vessel regulatory functions, such as hypertension, bleeding, thrombosis, and poor wound healing.8
Axitinib,9,10 cabozantinib,11,12 pazopanib,13 sorafenib,14 and sunitinib15 are Food and Drug Administration approved in advanced clear cell renal cell carcinoma treatment.
The Ras/Raf/Mek/Erk or mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) pathways are complex cell signaling pathways that depend on phosphorylation cascades to regulate transcription (Figure 11.3). The common driver mutation BRAF V600E is found in several cancers, such as melanoma, NSCLC, thyroid cancer, hairy cell leukemia, Langerhans cell histiocytosis, and ameloblastoma.16
BRAF inhibitor monotherapy is associated with acquired resistance, most commonly via reactivation of the MAPK pathway. Combining BRAF and MEK inhibitor therapy allows for complete inhibition of the MAPK pathway. Combination therapy with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) was found to improve PFS and overall survival (OS) compared to vemurafenib monotherapy (BRAF inhibitor) among patients with treatment-naïve metastatic V600E- or V600K-mutated melanoma.17
The anaplastic lymphoma kinase (ALK) gene located on chromosome 2 is prone to oncogenesis by forming fusions with several genes (Figure 11.4). The ALK-EML4 translocation produces a fusion gene that results in a constitutively active tyrosine kinase. This fusion protein serves as a driver mutation in 3% to 5% of cases of NSCLC, the overwhelming majority of which are adenocarcinomas.18 ALK-translocated NSCLC is highly sensitive to a number of small molecule inhibitors, including crizotinib,19,20 ceritinib,21 and alectinib.22–24 In 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for the use of the third-generation ALK inhibitor brigatinib for ALK-translocated NSCLC resistant to crizotinib.25 Brigatinib has clinically significant intracranial penetration in comparison to earlier generation ALK inhibitors.25 Lorlatinib is a third-generation ALK inhibitor that is approved for ALK-mutated NSCLC that is refractory to treatment with prior generation ALK inhibitors.26
The B-cell receptor (BCR)-ABL1 (ABL) reciprocal translocation occurs between the ABL1 gene of chromosome 9 and BCR gene of chromosome 22. The resulting hybrid chromosome (Philadelphia chromosome) results in a constitutively active tyrosine kinase (Figure 11.5). The fusion protein can occur at breakpoint position 190 (p190) or 210 (p210). The p190 product is more common in acute lymphoblastic leukemia (ALL) and the p210 product is more common in chronic myeloid leukemia (CML). The Philadelphia chromosome occurs in approximately 20% to 30% of all adults and less than 5% of children with ALL,27 while it is found in more than 95% in CML. The BCR-ABL inhibitors imatinib, dasatinib, and nilotinib are among the most effective treatments for Philadelphia chromosome–positive malignancies.28 Resistance to TKIs can occur, and the third-generation TKI ponatinib is indicated for the treatment of T3151-mutated CML and ALL.29 The major side effect of ponatinib is thrombosis.30
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are essential enzymes for oxidative phosphorylation as part of the Krebs cycle. IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate (α-KG). Mutated IDH1 and IDH2 lead to gain-of-function activity in some myeloid malignancies, such as acute myeloid leukemia (AML), brain tumors, chondrosarcoma, intrahepatic cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutated IDH cannot catalyze this reaction and instead catalyzes the reduction of α-KG to 2-hydroxyglutarate (2-HG). 2-HG is normally present in a very low concentration within the cell and its accumulation leads to suppression of the epigenetic enzyme ten-eleven translocation 2 (TET2). Suppression of TET2 inhibits DNA demethylation, gene activation, and cell differentiation. The result is hypermethylation, blockage of myeloid differentiation, and enhanced cell survival. TET2 mutation has similar effects. The IDH1 inhibitor ivosidenib31 is used in newly diagnosed and relapsed or refractory IDH1-mutated AML. The IDH2 inhibitor enasidenib32 is used in relapsed or refractory IDH2-mutated AML (Figure 11.6).
BCR activation induces a series of signaling cascades that lead to activation of transcription factors that promote cell survival and proliferation. The Bruton TKI ibrutinib is used for a number of non-Hodgkin lymphomas,33–36 chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),37,38 and Waldenström macroglobulinemia (WM).39 The phosphoinositide 3-kinase (PI3K) inhibitors copanlisib,40 duvelisib,41 and idelalisib42,43 are used for the treatment of CLL/SLL and follicular lymphoma (Figure 11.7).
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal transduction pathway is a complex network of receptors and proteins involving four different JAK proteins and seven different STAT proteins. Binding of ligand s (e.g., erythropoietin) to JAK receptors leads to receptor dimerization, phosphorylation, and STAT dissociation. Activated STAT proteins heterodimerize or homodimerize and translocate from the cytosol to the cell nucleus and affect transcription. The JAK-STAT pathway is involved in development, immunity, and cell death. Mutations in this pathway are found in a number of cancers, such as leukemia, lymphoma, breast cancer, prostate cancer, and melanoma. The single nucleotide JAK2 V617F mutation is found in the majority of patients with polycythemia vera (PV) and leads to erythropoietin-independent red blood cell production.44 The small molecule inhibitor ruxolitinib inhibits JAK1 and JAK2 and is used for the treatment of myeloproliferative neoplasms (MPN), such as PV45 and primary myelofibrosis (Figure 11.8).46,47
The FMS-like tyrosine kinase 3 (FLT3) receptor is a tyrosine kinase that is expressed on the surface of many hematopoietic progenitor cells. Binding of two FLT3 ligand s forms a bridge that brings the FLT3 receptors in close proximity to one another and activates transphorylation. Mutations in either the juxtamembrane domain (internal tand em duplication [AITD]) or the TKD of FLT3 leads to constitutive activity and cell survival. Approximately 30% of cases of AML harbor a FLT3 mutation. The multikinase (including FLT3) inhibitor midostaurin is frequently added to induction chemotherapy regimens for patients that harbor a FLT3 mutation.48 Gilteritinib is a FLT3 inhibitor that is approved for relapsed or refractory AML (Figure 11.9).49
Protein kinases are enzymes that transfer the terminal phosphate of ATP to substrates that usually contain a serine, threonine, or tyrosine residue. Kinases share a conserved arrangement of secondary structure elements that fold into a characteristic twin-lobed catalytic core structure with ATP binding in a deep cleft located between the lobes. Protein kinases can be tyrosine kinase (e.g., ALK, EGFR family, platelet-derived growth factor receptor [PDGFR]α/β, vascular endothelial growth factor receptor [VEGFR] family, c-MET, RET, FLT3, BCR-ABL, Bruton tyrosine kinase [BTK] and JAK family, Scr family) or serine/threonine kinase (e.g., CDK family, B-Raf, mTOR). Kinases can be receptor kinases (e.g., FLT3) or intracellular (e.g., JAK; Figure 11.10).
Classification of protein kinase inhibitors based upon the structures of their drug–enzyme complexes includes:
A deep understand ing of the molecular pathways described in this chapter provides a foundation for hematologists and medical oncologists to comprehend the currently available armamentarium and clinical applications of commonly used targeted therapies. Newer, more potent drugs are in development and will continue to exploit alterations in these pathways that allow cancer cells to arise, proliferate, and metastasize. Combination therapies with multiple targeted agents are used in certain situations to enhance drug efficacy or overcome acquired resistance mechanisms that allow tumor cells to bypass and surmount the action of targeted therapies. Targeted therapies can be highly effective because these therapies limit damage to noncancerous cells and reduce toxicity, as compared to traditional cytotoxic chemotherapy. As our understand ing of molecular changes in tumorigenesis grows and more specific and effective treatments for cancers driven by molecular alterations are developed, the targeted therapy armamentarium will continue to increase in diversity and specificity for tumors driven by molecular derangements.