Chapter 4: Growth factor signaling and oncogenes (Book 4.3)

Question 1

What member of the EGFR family is amplified in 30% of breast cancer patients and has a causal role in breast cancer?

Answer 1

ErbB2

Question 2

What kind of inhibitors are used in drugs directed against the tyrosine kinase acitivity of EGFR family members?

Answer 2

Small molecule kinase inhibitors

Question 3

What are the names of drugs directed against tyrosine kinase activity of EGFR family members?

Answer 3

Iressa (gefitinib), Tarceva (erlotinib) and Tykerb (lapatinib)

Question 4

Iressa (gefitinib) and Tarceva (erlotinib) are first-generation inhibitors. What does this mean?

Answer 4

Their binding is competitive and reversible (ATP can compete for their binding).

Question 5

Gilotrif (afatinib) is also a drug directed against tyrosine kinase activity of EGFR family members, but is a second-generation inhibitor. What does this mean?

Answer 5

It can form a covalent bond with EGFR, this binding is irreversible.

Question 6

What drugs are also used for treatment of advanced non-small-cell lung cancer?

Answer 6

Gilotrif (afatinib)

Question 7

The response rate to both Tarceva (erlotinib) and Gilotrif (afatinib) is quite high (70%), what is still a problem?

Answer 7

Development of drug resistance.

Question 8

What mutation in EGFR causes this resistance?

Answer 8

T790M. (Even though afatinib showed promise against T790M in early pre-clinical traisl, both drugs are not effective for this mutation. But there are second-generation mutant-selective covalent inhibitors being developed that target T790M and have entered clinical trials).

Question 9

A different approach has also proved succesful. Instead of targeting the tyrosine kinase domain of the ErbB2 receptor, what else can be targeted and with what?

Answer 9

The extracellular domain of the ErbB2 receptor can be targeted using monoclonal antibodies.

Question 10

Name a humanized monoclonal antibody that can be used against the extracellular domain of ErbB2 recptor.

Answer 10

Herceptin (trastuzumab)

Question 11

What mechanisms does Herceptin (trastuzumab) have in order to function?

Answer 11

Enhanced receptor degradation, inhibition of angiogenesis and recruitment of immune cells (resulting in antibody-dependent cellular cytotoxicity).

Question 12

Fill in:
Herceptin is meant for treatment of metastatic …. (1) cancer whose tumor overexpress ErbB2. Erbitux (cetuximab) and Vectibix (panitumumab) are also monoclonal antibodies that target EGFR and have been approved to treat … (2) cancer.

Answer 12

1. breast

2. colorectal

Question 13

Why do patients with KRAS mutations in their tumors not respond to Erbitux (cetuximab) and Vectibix (panitumumab)?

Answer 13

Because these monoclonal antibodies are directed against the extracellular domain of EGFR. KRAS is a downstream transducer protein of EGFR signaling. So if KRAS is mutated, KRAS becomes the oncogenic signal. It would then be in vain to block the signal of EGFR, if the oncogenic signal isn’t derived from this.

Question 14

Why are particular mutations in the EGFR gene more common in Japanese than Americans?

Answer 14

It may be due to a lifestyle factor, such as exposure to a specific carcinogen or a genetic predisposition (or both).

Question 15

What is the most commonly mutated onocogene in cancer?

Answer 15

Ras (therefore Ras is ideally a most important drug target)

Question 16

What is the function of an allosteric inhibitor of (G12C) K-Ras?

Answer 16

The allosteric inhibitor irreversibly binds to the mutant protein K-Ras, selectively binds the GDP form of the oncoprotein and interferes with Raf binding.

Question 17

Is targeting downstream Ras effectors valuable as a cancer treatment?

Answer 17

Yes!

Question 18

Nexavar (sorafenib) was approved for treatment of advanced renal cell carcinoma and hepatocarcinoma. What kind of drug is this?

Answer 18

A multi-kinase inhibitor that targets the ATP-binding site of Raf. This results in a reduction in downstream MAPK phosphorylation.

Question 19

What is important to monitor when administering a drug like sorafenib?

Answer 19

Molecular endpoints like MAPK activity, in addition to clinical endpoints (anti-tumor activity).

Question 20

What are two other Raf inhibitors that can be used in the treatment of melanoma?

Answer 20

Zelboraf (vemurafenib) and Tafinlar (dabrafenib).

Question 21

Fill in:

Half of all melanomas contain the … (1) mutation that leads to constitutive … (2) activity.

Answer 21

1. V600E

2. Kinase

Question 22

Zelboraf (Vemurafenib) induced partial or complete tumor regression. What is still a problem with this drug and how does this occur?

Answer 22

Drug resistance, it occurs due to the switch to other MEK kinases. (This suggests that combination treatments may be more effective for durable responses).

Question 23

Chronic myelogenous leukemia (CML) accounts for 15-20% of all leukemias. Most of CML patients (95%) carry the Philadelphia chromosome, what is this?

Answer 23

A product of chromosomal translocation generating the BCR-ABL fusion protein.

Question 24

What connection is there between BCR-ABL fusion protein and leukemia?

Answer 24

Due to the fusion protein, the tyrosine kinase activity of ABL is constitutive. As a result of aberrant kinase signaling, there is abnormal proliferation of white blood cells, the hallmark of leukemia.

Question 25

What drug has been successful in the treatment of chronic myelogenous leukemia (CML)?

Answer 25

Gleevec (imatinib), a small molecule tyrosine kinase inhibitor

Question 26

What can Gleevec (imatinib) also inhibit?

Answer 26

Besides tyrosine kinases, it can also inhibit ABL and c-KIT.

Question 27

CML has three disease phases: chronic (lasting 3-5 years), accelerated (lasting 3-9 months) and blast crisis (lasting 3-6 months). Why is this important to know?

Answer 27

As disease progresses, also the number of white blood cells increases. The effectiveness of Gleevec (imatinib) decreases with advanced disease phase.

Question 28

What is one of the reasons why the effectiveness of Gleevec decreases as disease progresses?

Answer 28

Reactivation of the kinase activity due to mutation or BCR-ABL amplification.

Question 29

What is oncogene addiction?

Answer 29

The dependence of cancer cell on a specific oncogene for its maintenance.