Podcast
Questions and Answers
What may constitutive and deregulated CDK activation contribute to in cancer cells?
What may constitutive and deregulated CDK activation contribute to in cancer cells?
- Apoptosis
- DNA repair
- Chromosomal instability and unscheduled proliferation (correct)
- Genomic stability
What is the effect of inhibiting ATM in vitro in the presence of mutations in other DNA damage repair genes?
What is the effect of inhibiting ATM in vitro in the presence of mutations in other DNA damage repair genes?
- Induces cell proliferation
- Induces synthetic lethality (correct)
- Has no effect on cell growth
- Induces apoptosis
Which type of cancer has been shown to be susceptible to inhibition of ATR?
Which type of cancer has been shown to be susceptible to inhibition of ATR?
- Breast cancer
- Colorectal cancer
- Leukemia
- Non-small cell lung cancer (correct)
What is the definition of synthetic lethality?
What is the definition of synthetic lethality?
Which gene was introduced in the concept of synthetic lethality?
Which gene was introduced in the concept of synthetic lethality?
What is the role of DNA damage-control protein kinases?
What is the role of DNA damage-control protein kinases?
What is the average number of genes bearing somatic mutations in common solid tumors?
What is the average number of genes bearing somatic mutations in common solid tumors?
What percentage of somatic mutations are single-base substitutions?
What percentage of somatic mutations are single-base substitutions?
What is the concept of oncogene addiction a consequence of?
What is the concept of oncogene addiction a consequence of?
Approximately how many genes can promote or drive tumorigenesis when mutated?
Approximately how many genes can promote or drive tumorigenesis when mutated?
What is the term used to describe genes altered in a high percentage of tumors?
What is the term used to describe genes altered in a high percentage of tumors?
What is the reason for MCF-7 cells being sensitive to rapamycin?
What is the reason for MCF-7 cells being sensitive to rapamycin?
What is the function of the chimeric BCR-ABL tyrosine kinase in chronic myelogenous leukemia (CML)?
What is the function of the chimeric BCR-ABL tyrosine kinase in chronic myelogenous leukemia (CML)?
What is the function of Ras in RTK signaling?
What is the function of Ras in RTK signaling?
What is the range of mutated driver genes present in a tumor?
What is the range of mutated driver genes present in a tumor?
What is the mechanism of action of Imatinib in chronic myelogenous leukemia (CML)?
What is the mechanism of action of Imatinib in chronic myelogenous leukemia (CML)?
What is the result of re-establishing the wt protein (ras or PI3K) in dld1 and hct116 cells?
What is the result of re-establishing the wt protein (ras or PI3K) in dld1 and hct116 cells?
What is the ultimate effect of the MAP/ERK kinase cascade?
What is the ultimate effect of the MAP/ERK kinase cascade?
Which of the following is a characteristic of the progression of colorectal cancer?
Which of the following is a characteristic of the progression of colorectal cancer?
What is the term used to describe the number of somatic mutations in a tumor?
What is the term used to describe the number of somatic mutations in a tumor?
What is the cellular response to Ras activation of the MAP/ERK kinase cascade?
What is the cellular response to Ras activation of the MAP/ERK kinase cascade?
What is a good example of gene addiction and escaping mechanisms?
What is a good example of gene addiction and escaping mechanisms?
What is the significance of oncogene addiction in cancer therapy?
What is the significance of oncogene addiction in cancer therapy?
Which of the following is NOT a type of signal transduction pathway altered in solid tumors?
Which of the following is NOT a type of signal transduction pathway altered in solid tumors?
What percentage of human tumors have mutations that permanently activate Ras?
What percentage of human tumors have mutations that permanently activate Ras?
What is the function of MEK kinase in the MAP/ERK kinase cascade?
What is the function of MEK kinase in the MAP/ERK kinase cascade?
Which of the following is NOT a downstream target of PI3K?
Which of the following is NOT a downstream target of PI3K?
What is the typical consequence of Ras mutations in cancer?
What is the typical consequence of Ras mutations in cancer?
What can lead to hyperactivation of PI3K?
What can lead to hyperactivation of PI3K?
Why can KRAS mutations lead to resistance to EGFR inhibitors?
Why can KRAS mutations lead to resistance to EGFR inhibitors?
What is a limitation of genomic and transcriptomic approaches in identifying driver kinases?
What is a limitation of genomic and transcriptomic approaches in identifying driver kinases?
What is a challenge in performing clinical trials for kinase inhibitors?
What is a challenge in performing clinical trials for kinase inhibitors?
What is a potential solution to overcoming resistance mechanisms in cancer treatment?
What is a potential solution to overcoming resistance mechanisms in cancer treatment?
What is a limitation of mass spectrometry-based approaches in identifying driver kinases?
What is a limitation of mass spectrometry-based approaches in identifying driver kinases?
What can occur if we do not fully understand the complexity of a given tumor type?
What can occur if we do not fully understand the complexity of a given tumor type?
How many kinases were listed as primary targets in clinical testing in 2010?
How many kinases were listed as primary targets in clinical testing in 2010?
Study Notes
Cancer Genome Landscapes
- Comprehensive sequencing efforts have revealed genomic landscapes of common human cancers
- These landscapes consist of a small number of "mountains" (genes altered in a high percentage of tumors) and a larger number of "hills" (genes altered not-so-frequently)
- Approx. 130 genes can promote or "drive" tumorigenesis when mutated
- A tumor can contain two to eight of these "mutated driver genes" – each mutated gene confers a small selective growth advantage
Altered Signal Transduction Pathways in Solid Tumors
- Nearly all RTKs signal via Ras/MAP kinase pathways
- Ras is a monomeric (small) GTPase-switch protein that propagates signaling further inside the cell via a kinase cascade that culminates in the activation of members of the MAP kinase family
- Mutant RTKs or Ras/MAP kinase signaling proteins are associated with nearly all cancers
- The 3 Ras genes in humans (HRas, KRas, and NRas) are the most common oncogenes in human cancer
RTKs and Ras/MAP Kinase Signaling
- Ras activates MAP kinase via a phosphorylation cascade that proceeds from Ras to Raf kinase, to MEK kinase, and finally to MAP kinase
- MAP kinase then dimerizes and enters the nucleus
- The cellular response includes Proliferation, Growth, Invasion, Metastasis, Resistance to cell death, and Angiogenesis
Targeting Protein Kinases in Cancer Therapy
- The concept of oncogene addiction is a consequence of the fact that the multistage process of carcinogenesis is not simply a summation of the individual effects of activation of multiple oncogenes and inactivation of multiple tumor suppressor genes
- Oncogene addiction refers to the curious observation that some cancer cells, despite their plethora of genetic alterations, can seemingly exhibit dependence on a single or a few gene products for their sustained proliferation and/or survival
- Therapeutic targeting of PKs has been successful in chronic myelogenous leukemia (CML) and Imatinib
- Targeting one kinase with multiple drugs is a good example of gene addiction and escaping mechanisms
Challenges/Limitations
- Genomic and transcriptomic approaches have identified many driver kinases in human cancer, but the picture is incomplete as protein kinases are regulated at multiple levels
- Mass spectrometry-based approaches have limitations as well – low abundant proteins and/or post-translational modifications
- The risk is that we underestimate the complexity of a given tumor type also from a therapeutic point of view
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Description
Explore the altered signal transduction pathways in solid tumors, including EGFR, RAS, PI3K/AKT/mTOR, MAPKs, and CDKs. Learn how protein kinases are targeted in cancer therapy.
