In this discussion, we will go over small molecules and tyrosine kinase inhibitors that are used in cancer treatments
Introduction to Small Molecules
When we’re talking about small molecules, we really mean small. These molecules are small than even monoclonal antibodies. Because of this, they tend to infer effects from inside the cell rather than outside the cell.
Most are oral agents. This is because smaller molecules are not broken down in the gut.
Unlike cell-cycle agents that are dosed purely based on BSA, these agents are dosed based on BSA, mg/kg, or flat dosing.
Also, unlike cell-cycle agents, where they’re non-specific, these agents target specific targets. Some target specific mutations (oncogenes), but this doesn’t mean you will always hit cancer cells. This also means that they aim to cause dysfunctions in that specific target, not necessarily cell-kill. As such, many of these agents are used as the last line to slow and prevent the progression of the diseases with no improvement expectation.
There are many classes that we will go over today. I try to group them by their targets. The largest group is classes that target a receptor or protein within the EGFR pathway. There are five classes here. Then we will talk about two other classes that also target a specific receptor: VEGFR and Hedgehog. After this, we will move into classes that cause cell cycle disruption: mTOR and cell-cyle agents. Next, we venture to another class with a completely different pathway that also targets protein within the cell: BCR-Abl. Now that we’re done with the cytoplasm, we go in deeper into classes that interfere with the DNA synthesis process: PARP and HDACi. And lastly, we go to the clean-up crews. These classes are proteosome inhibitors and BCL-2.
Epidermal Growth Factor Receptor (EGFR) pathway
EGFRs are receptors that are on epidermal cells. They are highly concentrated in the skin and the guts. Normally, a growth factor is needed to activate EGFR, dimerize the receptor, and cause downstream effects. A mutation within EGFR allows EGFR to be activated without the binding of the growth factor, leading to overexpression. This results in increased cell growth, metastasis, and apoptosis resistance. One of the most mutations of the EGFR is the EGFR T790M mutation, which is seen mostly in lung cancer (50-80% of lung cancer).
The EGFR pathway starts with EGFR activation at the membrane. This is followed by downstream activation of RAS –> B-RAF –> MEK –> MAPK –> RSK1. There can be mutations at any point of this pathway that ultimately result in overexpression and uncontrolled cell growth. As such, several classes were invented to target these mutations along this pathway.
- EGFR inhibitors target EGFR
- ALK inhibitors target a fusion protein that works with EGFR to activate RAS.
- Her2/neu inhibitors target EGFR and Her2.
- B-RAF inhibitors target B-RAF.
- MEK inhibitors target MEK.
There are some caveats with B-RAF inhibitors and MEK inhibitors, which we will discuss later in this discussion. But first, let’s start with EGFR inhibitors.
Epidermal Growth Factor Receptor Inhibitors -“Acneiform”
Agents: Erlotinib, osimertinib, afatinib, gefitinib, dacomitinib, and mobocertinib
Indication: Mostly lung cancers – osimertinib targets the EGFR T790M mutation. Erlotinib targets exon 19 deletion or exon 21 substitution mutations.
Class ADRs: Because EGFRs are highly concentrated in the skin and gut tissues, most of the unique ADRs are concentrated in these locations: diarrhea and dermatologic toxicities (Acneiform – starts 1-week post dose – patients need prophylaxis moisturizer and sunscreen). A rare ADR is interstitial lung disease (from the epidermal tissue in the lungs)
Unique agent indications: Erlotinib – CYP2C9 substrate and can be affected by smoking. The dose must be increased to compensate for the induced metabolism. Also, erlotinib required an acidic environment to work, and any medication that reduces the acidity of the stomach (PPI, H2RA, antacids) should be avoided. If they have to be used, H2RA (famotidine) is preferred due to their short duration of action.
Anaplastic Lymphoma Kinase (ALK) Inhibitors – “Trailing Effect”
Agents: Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib.
Indication: Lung cancer
These agents target the EML4-ALK fusion oncogene (ALK mutation) that works with EGFR to activate the RAS pathway. By inhibiting this, we take away RAS activation, which is the pathway that causes the inhibition of apoptosis.
The EML4-ALK mutation is found in 2-10% of lung cancer, especially in non-smokers. Typically, we do not see both EGFR mutation and ALK mutation at the same time.
Crizotinib works very well, and patients can see a drastic improvement. But, resistance can develop, and once this happens, cancer will progress very rapidly.
Class ADRs: QT prolongation, hepatotoxicity, and GI toxicity
Crizotinib ADRs: vision changes (certain color blinding and trailing effect) and hypogonadism
Her2/neu Inhibitors – “oral trastuzumab”
Agents: Lapatinib, neratinib, and tucatinib
Indications: Her2 positive metastatic breast cancer (Her2 is overexpressed in 25% of breast cancers)
These agents have a dual mechanism that works on both EGFR and Her2.
Her2 is part of cardiovascular tissues and is responsible in part for cardiac contraction. Overexpression of Her2 can lead to cardiac issues (reversible) and chronic heart failure.
Class ADRs: cardiovascular issues (decreased left ventricular ejection fraction), diarrhea, rash, hand-foot syndrome.
Rapidly Accelerating Fibrosarcoma Type B (B-RAF) Inhibitors – “combine with MEKi”
Agents: Dabrafenib, vemurafenib, and encorafenib
Indications: metastatic melanoma (non-wildtype)
Dabrafenib blocks the MAP kinase pathway to half uncontrolled growth. It targets the V600E and V600K mutations.
Class ADRs: photosensitivity (skin cancer), diarrhea, musculoskeletal issues. New primary squamous cell cancer risk can be reduced when given with MEKi.
MAPK/ERK Kinase (MEK) Inhibitors – “retinopathies”
Agents: Trametinib, cobimetinib, and binimetinib
Indications: metastatic melanoma (non-wildtype)
These agents work through the same pathway as BRAF and can be used as either monotherapy or with BRAF inhibitors for BRAF V600E or V600K mutations. Another benefit of using BRAF inhibitors can reduce resistance risk.
It is important to note that BRAFi and MEKi pairings are specific. Mostly because a pair is typically manufactured by the same manufacturer, and they were studied together.
Why BRAF should be given with MEKi? If only BRAF is blocked, our smart body can find an alternate route to push the pathway through (through MEKK5, ROCK2, STR3, or RB typically), leading to an increased risk of basal cell carcinoma.
Class ADRs: Same as BRAF inhibitors except for retinopathies (UV melanoma)
Other Small Molecules Targeting Receptors – VEGFR and Hedgehog
Vascular Endothelial Growth Factor Receptor Inhibitors (VEGFRi) – “angiogenesis”
Agents: Sorafenib, sunitinib, axitinib, pazopanib, and tivozanib
Indications: Many! Started in kidney cancer and is now being used for soft tissue sarcoma, thyroid cancer, gastrointestinal stromal tumor, pancreatic neuroendocrine tumors, etc.
These agents all target VEGFR but also target other tyrosine kinases. The ultimate goal is to block angiogenesis. As the tumor gets bigger, it needs more blood supply. If the blood supply is blocked, the tumor cannot grow.
Class ADRs: Because the effect of blocking angiogenesis is not specific, this occurs all over the body, leading to hypertension and clotting problem. The heart cannot compensate for hypertension, which can lead to kidney damage. The clotting problem can lead to bleeding, thrombosis risks, and wound healing. Another unique ADR is the hand-foot syndrome (different from 5-FU). This tends to be more hyper-keratotic, especially in a high-friction area. A treatment with urea-containing moisturizer is recommended. TSH needs to be monitored due to thyroid toxicity. Hepatotoxicity.
Hedgehog Inhibitors – “Cyclopia”
Agents: Vismodegib, sonidegib, and glasdegib
Indication: basal cell carcinoma and acute myeloid leukemia (rare)
These agents work by binding to the smoothened pathway transmembrane receptor and prevent the downstream effects of the Hedgehog pathway. This pathway is abnormally activated in basal cell carcinomas.
The Hedgehog pathway is crucial in embryonal development. It plays a role in head-tail differentiation, which is why hedgehog inhibitors are very teratogenic and has a BBW for embryofetal toxicity. Usage during pregnancy can lead to cyclopia. Patients cannot donate blood for at least 7 months after therapy.
Class ADRs: Cyclopia, taste changes, arthralgia, and myalgias
Agent ADRs: Sonidegib – bad musculoskeletal ADRs, if CK is elevated, dose adjustment is required.
Classes that target cell cycles: mTORi and cyclin dependant kinase 4&6
Mammalian Target of Rapamycin (mTOR) Inhibitors
Agents: Everolimus and temsirolimus
Indications: Kidney and pancreatic neuroendocrine cancers
Everolimus is a derivative of sirolimus, which is used in transplantation. It works on the mTOR pathway, which is an important regulator of the cell cycle. This leads to cell cycle arrest and a decrease in proteins, such as VEGF.
Class ADRs: rash, mucositis, hyperglycemia, hyperlipidemia, and hypertriglyceridemia.
Temsirolimus is diluted with polysorbate 80 like taxanes, which means an infusion reaction and must be premedicated with diphenhydramine.
Cyclin Dependant Kinases 4&6 – “G1 target”
Agents: Palbociclib, abemaciclib, and ribociclib
Indication: Estrogen receptor (+) breast cancers
These agents inhibit cyclin-dependent kinases 4 and 6. Estrogen receptor (+) is especially sensitive to this class due to the growth factor.
Class ADRs: Due to the similarity in the mechanism of action, the ADRs of this class are very similar to those of cell-cycle specific agents: myelosuppression, nausea, vomiting, and diarrhea.
Unique ADRs: peripheral neuropathy and thromboembolic disorders.
Intracellular Target: Breakpoint Cluster Region – Abelson (BCR-Abl) inhibitors – “Point mutation efficacy”
Agents: Dasatinib, imatinib, nilotinib, ponatinib, boxutinib, and asciminib
Indications: There are many, but mainly CML.
These agents bind to BCR-Abl tyrosine kinase at the ATP binding domain and block the downstream effect. This leads to apoptosis. Like VEGFR, many of BCR-Abl inhibitors have multiple targets. (SRC, c-KIT, PDGFR, etc.)
These agents are very susceptible to a point mutation of the host. For example, if a T315I mutation occurs, it knocks out the ability of many of these agents to work, and only ponatinib is efficacious in this case.
Dasatinib and nilotinib rely on acidity for absorption – avoid with PPI.
One thing to note is that BCR-Abl has also been referred to as the Philadephia or p922. They are the same thing.
Class ADRs: NVD, musculoskeletal pain, myelosuppression, and periorbital fluid retention (give furosemide).
Unique ADRs: Nilotnib – highest CV toxicity. Dasatinib – highest fluid retention. Imatinib – worst diarrhea and musculoskeletal pain. Ponatinib – BBW for hepatotoxicity and thromboembolic events.
Classes that work with DNA synthesis
Moving on. We’re staying inside the cell, but digging deeper into the nucleus. Here are the agents that work with DNA synthesis: PARP inhibitors and HDAC inhibitors.
Poly (ADP-ribose) Polymerase (PARP) Inhibitors – “More common in BRCA mutation”
Agents: Olaparib, rucaparib, niraparib, and talazoparib
Indications: BRCA-mutated ovarian cancer
PARP is an enzyme responsible for the homeostasis of DNA repair. A dysfunction in PARP is often seen in BRCA-mutated lines. PARP inhibitors stop DNA repair, and they are not specific to cancer cells.
Class ADRs: NVD, myelosuppression (anemia), and embryo-fetal toxicity
Histone Deacetylase (HDAC) Inhibitors – “Not common”
Agents: Panobinostat, belinostat, romidepsin, and vorinostat.
Indications: Multiple myeloma
Class ADRs: QTc prolongation, NV, fatigue, and myelosuppression
Unique ADRs: Panobinostat – very severe diarrhea
The “Mop Up” Classes
Finally, the last subgroup belongs to those that do the “mop up” jobs: Proteosome inhibitors and BCL-2 inhibitors.
Proteosome Inhibitors – “Acyclovir prophylaxis”
Agents: Bortezomib, carfilzomib, and ixazomib
Indications: Multiple myeloma, mantle cell lymphoma
These agents work by blocking the 26S proteasome, resulting in the cell’s inability to clean up protein waste. The cell is overloaded with protein waste and proceeds through apoptosis.
Class ADRs: Thrombocytopenia, peripheral neuropathy (major ADR), edema, hypotension, cardiopulmonary toxicity, and herpes zoster reactions – patients must be on acyclovir prophylaxis.
Unique ADRs: bortezomib – SQ can reduce peripheral neuropathy compared to IV administration.
BCL-2 Inhibitor – “tumor lysis syndrome”
Agents: Venetoclax
Indications: hematological cancer, mostly leukemia
Venetoclax blocks BCL-2, which is the protein that blocks N-type apoptosis, thereby, inducing apoptosis.
Class ADRs: These cells die off very quickly, leading to high myelosuppression and tumor lysis syndrome.
This can be handled by slowly ramping up the dosing schedule.