Lec 3: Pharmacology of Targeted Cancer Therapies

Question 1

Cancer Arises from an Imbalance of Genetic Events

Answer 1

Question 2

Cancer Arises from an Imbalance of Genetic Events… talk about Oncogenes

Answer 2

• Become activated – gain of function mutations
• Often involved in cell signal transduction and cell death
  signaling (e.g., inhibition of apoptosis)
• Originally found in viruses – virus picks up protooncogene from host cell
• RED: Often provide druggable targets

Question 3

Cancer Arises from an Imbalance of Genetic Events… talk about Tumor Suppressor Genes

Answer 3

• Become inactivated – loss of function mutations
• Often involved in stabilizing genome, cell cycle regulation, and cell environment regulation
• Categorized as caretakers, gatekeepers, and landscapers
• RED: Difficult to target for pharmacotherapy

Question 4

Proto-Oncogenes and Normal Cell Growth

Answer 4

Question 5

Oncogenes are Mutant Forms of Proto-Oncogenes (PIC)

Answer 5

Question 6

Kinases – targets of kinase inhibitors (just know the general)

Answer 6

Question 7

Receptor Tyrosine Kinases

Answer 7

Question 8

Ways that oncogenes can become activated (6 ways)

Answer 8

1.) Chromosomal translocations – results in abnormal
expression or creates a chimeric protein with unique
activity
.
2.) Mutations – e.g., a point mutation that changes the
amino acid sequence of the coded protein
.
3.) Amplifications – multiple copies of a gene leading to
overexpression
.
4.) Dysregulation – e.g., overexpression due to mutations
in the promoter region
.
5.) Proviral insertion – viral insertion alters gene
expression
.
6.) Others – alterations in post-translation processes, such as phosphorylation

Question 9

Chromosomal Translocation – An Example

Answer 9

Question 10

BCR-ABL Kinase Inhibitors and Chromosomal Translocations

Answer 10

• Chronic Myeloid Leukemia
• Imatinib (Gleevec®), Dasatinib, Nilotinib, Bosutinib, Ponatinib
• Activation of the ABL oncogene occurs due to a
  translocation between chromosomes 9 and 22.

Question 11

Mutations: Example - KIT Mutations
…Mutations may be result in:

Answer 11

• Mutation of an oncogene – occurs as an early event in
  cancer development – often important for maintaining the cancer phenotype (Oncogene Addiction)!!
• Drug resistance – occur after drug therapy has been
  initiated – may take months or years to develop – require changing drug used to inhibit activity

Question 12

Epidermal Growth Factor Receptor (EGFR)

Answer 12

NOTE: Know that EGFR1 is the most important class…have a lot of pathways so chances of stuff going “wrong” is more! but will usually have 1 oncogenic event!

Question 13

Kinase Inhibitors: EGFR Inhibitors…know the most important one!!!

Answer 13

Question 14

Kinase Inhibitors: Ras Inhibitors – Sotorasib (LUMAKRAS®)

Answer 14

Sotorasib (LUMAKRAS®) - inhibits Ras (Kras) harboring a G12C mutation

Question 15

Kinase Inhibitors: BRAF Inhibitors

Answer 15

Dabrafenib (Tafinlar®) and Vemurafenib (Zelboraf®) are
BRAF inhibitors used in the treatment of melanoma. The
name “vemurafenib” comes from V600E mutated BRAF
inhibition

Question 16

Kinase Inhibitors: MEK Inhibitors

Answer 16

Cobimetinib (Cotellic®) and Trametinib (Mekinist®) are
MEK 1 & 2 inhibitors used in the treatment of melanoma.

Question 17

Kinase Inhibitors: Amplifications – Her2 / ErbB2

Answer 17

Question 18

Kinase Inhibitors: PI3K Inhibitors

Answer 18

PI3K inhibitors - Phosphoinositide 3- kinase (PI3K or PIK3CA) phosphorylates the 3’ hydroxyl group of the inositol ring of phosphatidylinositol involved in cell
signal transduction. Copanlisib (Aliqopa®) and Idelalisib (Zydelig®) are PI3K inhibitors used in the treatment of
certain blood cancers (e.g., CLL, SLL).

Question 19

Kinase Inhibitors: mTOR inhibitors

Answer 19

mTOR inhibitors - mammalian target of
rapamycin (mTOR) is a sensor of cellular
nutrient, oxygen, and energy levels and
integrates cell signals from cell signal
pathways. mTORC1 functions as a
nutrient, energy, and redox sensor and
controls protein synthesis. mTORC2
phosphorylates Akt. Everolimus
(Afinitor®) is an mTOR inhibitor used in
the treatment of breast cancer (in
combination with exemestane).

Question 20

Other Kinase Inhibitors Used as Cancer Chemotherapies: ALK inhibitors

Answer 20

(Anaplastic Lymphoma Kinase) Alectinib (Alecensa®), Brigatinib (Alunbrig®), Certinib (Zykadia®) are ALK
inhibitors and Crizotinib (Xalkori®) is a mutant ALK inhibitor used in the treatment of non-small cell lung cancer.

Question 21

Other Kinase Inhibitors Used as Cancer Chemotherapies: BTK inhibitors

Answer 21

Bruton’s tyrosine kinase (BTK) is a kinase with a
key role in B-cell development. Acalabrutinib (Calquence®) is a BTK inhibitor and Ibrutinib (Imbruvica®) is a mutant BTK inhibitor

Question 22

Other Kinase Inhibitors Used as Cancer Chemotherapies: CDK inhibitors

Answer 22

Cyclin-dependent kinases function in the
phosphorylation of proteins involved in cell cycle progression. Palbociclib (Ibrance®) is a cyclin-dependent kinase 4 & 6 inhibitor used in the treatment of ER+, HER2 negative breast cancer.

Question 23

Switching gears to Proteasome Inhibitors… what’s proteasome? what’s proteasome Inhibitors

Answer 23

Proteasome - ubiquitinated proteins are proteolytically
degraded in an ATP-dependent process mediated by the
multiprotein proteasome complex
.
Proteasome Inhibitors
* Bortezomib (Velcade®)
* Carfilzomib (Kyprolis®)
* Ixazomib (Ninlaro®)
.
NOTE: Cancer cells have specific AAs need..so it can mess with the proteasome/ have their effects alter to cater to the cancer cell’s need for survival/ growth!

Question 24

Hedgehog Signaling Pathway

Answer 24

Question 25

Miscellaneous Cancer Chemotherapies: Thalidomide analogs

Answer 25

Thalidomide analogs - Thalidomide, lenalidomide, and pomalidomide - induce tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and through immunomodulatory activity.
.
NOTE: this drug inhibit blood vessel development/ reduce o2 and food to cancer cell = death

Question 26

Miscellaneous Cancer Chemotherapies: PARP inhibitors

Answer 26

PARP inhibitors - Poly (ADP-ribose) polymerase (PARP) is a large group of proteins involved in DNA repair and apoptosis. Olaparib (Lynparza®) is a PARP inhibitor used in the treatment of ovarian and breast cancer.

Question 27

Miscellaneous Cancer Chemotherapies: Isocitrate dehydrogenase 2 inhibitors

Answer 27

Isocitrate dehydrogenase 2 inhibitors - Enasidenib (Idhifa®) is an inhibitor of mutant isocitrate dehydrogenase 2 used in the treatment of acute myeloid
leukemia.

Question 28

Miscellaneous Cancer Chemotherapies: Bcl-2 inhibitors

Answer 28

Bcl-2 inhibitors – The B-cell lymphoma 2 protein is an anti-apoptotic protein overexpressed in some cancers. Venetoclax (Venclexta®) is a Bcl-2 inhibitor used in the treatment of chronic lymphocytic leukemia.
.
NOTE: anti-apoptotic protein keeps cells from dying! Normal cells have a lifecycle and die when they are suppose to… cancer cells don’t really die/ live way too long b/c of overexpression of Bcl-2

Question 29

Miscellaneous Cancer Chemotherapies: HDAC inhibitors

Answer 29

HDAC inhibitors – Vorinostat (suberanilohydroxamic acid; Zolinza®) is ahistone deacetylase inhibitor used in the management of cutaneous T celllymphoma.

Question 30

Mechanisms of Resistance to Targeted Cancer Therapies
* Primary (inherent) resistance

Answer 30

• Resistance in absence of prior treatment with agent
• Mutations in susceptibility genes (e.g., p53)

Question 31

Mechanisms of Resistance to Targeted Cancer Therapies
* Acquired Resistance

Answer 31

• P-Glycoprotein (= MDR1, ABCB1) and other drug efflux pumps
• Increase in drug metabolizing pathways: Phase I enzymes, Phase II enzymes, or Glutathione
• Expression of an alternative target (e.g., c-met in place of EGFR)
• Deletion of drug target
• Mutations in target (and susceptibility genes [e.g., p53])
• Upregulation of target - increased expression – upregulation / amplification
• Upregulation of survival genes (e.g., antiapoptotic; autophagy; DNA repair enzymes)