Antineoplastic Drugs and Cancer Chemotherapy-III: Molecular Targeted Therapies

Comprehensive vocabulary flashcards covering the classes, mechanisms of action, clinical indications, adverse effects, and molecular targets of modern antineoplastic therapies presented in Cancer Chemotherapy-III.

Biologics

Antineoplastic agents derived from living cells or organisms characterized by a long half-life ($t_{1/2}$ of days to weeks), high on-target specificity, low oral bioavailability, higher manufacturing cost, and suitability for extracellular targets.

Small-Molecule Targeted Therapies

Chemically synthesized antineoplastic drugs with short half-lives ($t_{1/2}$ of hours to days), oral bioavailability, lower manufacturing cost, and the ability to cross cell membranes to inhibit intracellular targets.

Small-Molecule EGFR Inhibitors

Orally administered tyrosine kinase inhibitors, including erlotinib, gefitinib, afatinib, and osimertinib, indicated for non-small cell lung cancer (NSCLC); common adverse effects include skin rash, stomatitis, diarrhea, and interstitial lung disease.

Monoclonal Antibodies Targeting EGFR

Intravenously administered biologics, including cetuximab, panitumumab, and necitumumab, indicated for metastatic NSCLC and metastatic colorectal cancer harboring wild-type KRAS; adverse effects include skin rash, diarrhea, interstitial lung disease, infusion reactions, hypomagnesemia, and cardiopulmonary arrest.

Trastuzumab

A humanized IgG1 monoclonal antibody targeting the extracellular domain of HER2, indicated for HER2-positive breast cancer and gastric cancer; carries a major risk of congestive heart failure when combined with doxorubicin.

Pertuzumab

A humanized IgG1 monoclonal antibody targeting a distinct domain of HER2 to prevent dimerization with other HER family receptors; approved in combination with trastuzumab and a taxane for HER2-positive breast cancer.

Olaratumab

A fully human IgG1 monoclonal antibody against platelet-derived growth factor receptor (PDGFR), indicated in combination with doxorubicin for soft-tissue sarcoma; associated with neutropenia, thrombocytopenia, elevated aPTT, hypokalemia, and hypophosphatemia.

Vemurafenib

A B-Raf kinase inhibitor indicated for $BRAF^{V600E/K}$-mutant melanoma (ineffective in wild-type BRAF); associated with cutaneous adverse drug reactions in up to $60\%$ of patients, QT prolongation, arthralgia, and CYP1A2 inhibition.

Dabrafenib

A B-Raf kinase inhibitor indicated for $BRAF^{V600E/K}$-mutant melanoma and $BRAF^{V600E}$-mutant NSCLC (often combined with the MEK inhibitor trametinib); metabolized via CYP2C8 and CYP3A4.

Cobimetinib

A MEK inhibitor indicated for $BRAF^{V600E/K}$-mutant melanoma; adverse effects include diarrhea, photosensitivity, nausea, and risks of hemorrhage and cardiomyopathy.

Trametinib

A MEK inhibitor indicated with dabrafenib for $BRAF^{V600E/K}$-mutant melanoma and $BRAF^{V600E}$-mutant NSCLC; ineffective after resistance to BRAF inhibitors develops, and exhibits reduced absorption after a high-calorie meal.

Ruxolitinib

A Janus-associated kinase (JAK) inhibitor that suppresses hematopoietic cell proliferation caused by overactive JAK signalling; approved for polycythemia vera and myelofibrosis, frequently causing thrombocytopenia and anemia.

CDK 4/6 Inhibitors

A class of oral inhibitors comprising palbociclib, abemaciclib, and ribociclib, used in combination with antiestrogens for advanced $ER^+$, $HER2^-$ breast cancer to prevent Rb phosphorylation and arrest the cell cycle in $G_0$ and $G_1$.

Philadelphia Chromosome

An abnormal chromosome 22 resulting from a reciprocal translocation with chromosome 9 ($t(9;22)$), generating the constitutively active $BCR\text{-}ABL$ fusion oncogene that drives chronic myeloid leukemia (CML).

Imatinib

A first-generation tyrosine kinase inhibitor targeting BCR-ABL, indicated for chronic-phase CML, KIT-positive GIST, KIT-positive mucosal and acral lentiginous melanoma, DFSP, and CMML; common adverse effects include fluid retention and gastrointestinal toxicity.

Ponatinib

A third-generation multi-targeted tyrosine kinase inhibitor uniquely active against the refractory $T315I$ gatekeeper mutation of BCR-ABL.

Everolimus

An oral mTOR inhibitor indicated for renal cell carcinoma, advanced $ER^+$, $HER2^-$ breast cancer (with aromatase inhibitors), primitive neuroectodermal tumors (PNETs), and progressive neuroendocrine GIST; substrate of CYP3A4.

Temsirolimus

An intravenous mTOR inhibitor indicated for renal cell carcinoma; associated with cutaneous adverse reactions, leukopenia, thrombocytopenia, and interstitial lung disease.

Bevacizumab

A humanized IgG1 monoclonal antibody targeting VEGFA to inhibit tumor angiogenesis; approved for metastatic colorectal cancer, NSCLC, glioblastoma, and ovarian cancer; requires delaying elective surgery for 1 month due to impaired wound healing.

Ramucirumab

A fully human IgG1 monoclonal antibody that directly targets the extracellular domain of VEGFR2; indicated for metastatic colorectal cancer, advanced gastric adenocarcinoma, and NSCLC.

Aflibercept

A recombinant fusion protein composed of the binding domains of VEGFR1 and VEGFR2 fused to the Fc portion of human IgG1, functioning as a soluble decoy trap for VEGF ligands in metastatic colorectal cancer.

Sunitinib

An oral multi-kinase inhibitor targeting VEGFR and other kinases, approved for metastatic renal cell cancer, imatinib-resistant GIST, and pancreatic neuroendocrine tumors; adverse effects include hypertension, bleeding, fatigue, and hypothyroidism.

Immune Checkpoints

Inhibitory receptor-ligand pathways (such as CTLA-4/CD80 and PD-1/PD-L1) that normally prevent autoimmunity by limiting T-cell activation, but are exploited by tumor cells to evade immune surveillance.

Ipilimumab

A fully human IgG1 monoclonal antibody targeting CTLA-4, indicated for metastatic melanoma, renal cell carcinoma, NSCLC, and hepatocellular carcinoma; causes autoimmune-mediated toxicities in $>70\%$ of patients (e.g., colitis, pruritus, hypophysitis).

Nivolumab

A fully human IgG4 monoclonal antibody targeting PD-1, indicated for advanced melanoma, previously treated NSCLC, advanced RCC, and relapsed/refractory Hodgkin lymphoma; can trigger immune-related pneumonitis, colitis, and endocrinopathies.

Pembrolizumab

A humanized IgG4 monoclonal antibody targeting PD-1 approved across $>25$ distinct cancer indications (including melanoma, NSCLC, and urothelial carcinoma) to restore anti-tumor T-cell activity.

Synthetic Lethality

A therapeutic strategy wherein cell death occurs only when two distinct pathways are concurrently inactivated (such as combining an innate BRCA mutation in homologous recombination with pharmacological PARP inhibition).

Olaparib

A poly (ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in tumors harboring DNA repair defects (e.g., BRCA mutations) in ovarian, breast, and prostate cancer.

Antibody-Drug Conjugates (ADCs)

Therapeutic constructs combining a targeted monoclonal antibody linked via a chemical linker to a cytotoxic payload (toxin), ensuring selective drug delivery directly to tumor cells.

Trastuzumab Deruxtecan

An antibody-drug conjugate comprising a HER2-directed monoclonal antibody coupled to a topoisomerase I inhibitor payload, approved for HER2-positive and HER2-low breast cancer, gastric, NSCLC, and colorectal cancers.

Polatuzumab Vedotin

An antibody-drug conjugate comprising an anti-CD79b antibody coupled to a microtubule polymerization inhibitor payload, indicated for diffuse large B-cell lymphoma (DLBCL).