Cancer Biology: Signal Transduction Pathways
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Cancer Biology: Signal Transduction Pathways

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Questions and Answers

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?

  • 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?

  • Breast cancer
  • Colorectal cancer
  • Leukemia
  • Non-small cell lung cancer (correct)

    • What is the definition of synthetic lethality?

    <p>When a combination of deficiencies in the expression of two or more genes leads to cell death</p> Signup and view all the answers

    Which gene was introduced in the concept of synthetic lethality?

    <p>PARP</p> Signup and view all the answers

    What is the role of DNA damage-control protein kinases?

    <p>To repair DNA damage</p> Signup and view all the answers

    What is the average number of genes bearing somatic mutations in common solid tumors?

    <p>33-66 genes</p> Signup and view all the answers

    What percentage of somatic mutations are single-base substitutions?

    <p>95%</p> Signup and view all the answers

    What is the concept of oncogene addiction a consequence of?

    <p>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</p> Signup and view all the answers

    Approximately how many genes can promote or drive tumorigenesis when mutated?

    <p>130 genes</p> Signup and view all the answers

    What is the term used to describe genes altered in a high percentage of tumors?

    <p>Mountains</p> Signup and view all the answers

    What is the reason for MCF-7 cells being sensitive to rapamycin?

    <p>They carry activated PI3K which hyper-stimulates mTOR</p> Signup and view all the answers

    What is the function of the chimeric BCR-ABL tyrosine kinase in chronic myelogenous leukemia (CML)?

    <p>To transfer phosphate from ATP to tyrosine residues on various substrates to cause excess proliferation of myeloid cells</p> Signup and view all the answers

    What is the function of Ras in RTK signaling?

    <p>It propagates signaling further inside the cell via a kinase cascade</p> Signup and view all the answers

    What is the range of mutated driver genes present in a tumor?

    <p>2-8 genes</p> Signup and view all the answers

    What is the mechanism of action of Imatinib in chronic myelogenous leukemia (CML)?

    <p>It blocks the binding of ATP to the BCR-ABL tyrosine kinase</p> Signup and view all the answers

    What is the result of re-establishing the wt protein (ras or PI3K) in dld1 and hct116 cells?

    <p>It slightly discourages cell proliferation</p> Signup and view all the answers

    What is the ultimate effect of the MAP/ERK kinase cascade?

    <p>Phosphorylation of transcription factors that regulate genes involved in cell cycle regulation and differentiation</p> Signup and view all the answers

    Which of the following is a characteristic of the progression of colorectal cancer?

    <p>It is a good model for cancer</p> Signup and view all the answers

    What is the term used to describe the number of somatic mutations in a tumor?

    <p>Ticking clock</p> Signup and view all the answers

    What is the cellular response to Ras activation of the MAP/ERK kinase cascade?

    <p>Proliferation, Growth, Invasion, Metastasis, Resistance to cell death, Angiogenesis</p> Signup and view all the answers

    What is a good example of gene addiction and escaping mechanisms?

    <p>Targeting one kinase with multiple drugs</p> Signup and view all the answers

    What is the significance of oncogene addiction in cancer therapy?

    <p>It provides a target for therapy that can be exploited to kill cancer cells</p> Signup and view all the answers

    Which of the following is NOT a type of signal transduction pathway altered in solid tumors?

    <p>NF-kB</p> Signup and view all the answers

    What percentage of human tumors have mutations that permanently activate Ras?

    <p>20% to 25%</p> Signup and view all the answers

    What is the function of MEK kinase in the MAP/ERK kinase cascade?

    <p>It phosphorylates MAP kinase</p> Signup and view all the answers

    Which of the following is NOT a downstream target of PI3K?

    <p>RTKs</p> Signup and view all the answers

    What is the typical consequence of Ras mutations in cancer?

    <p>Permanent activation of Ras</p> Signup and view all the answers

    What can lead to hyperactivation of PI3K?

    <p>Blocking mTOR with Rapamycin</p> Signup and view all the answers

    Why can KRAS mutations lead to resistance to EGFR inhibitors?

    <p>Because KRAS mutations are downstream of EGFR</p> Signup and view all the answers

    What is a limitation of genomic and transcriptomic approaches in identifying driver kinases?

    <p>They are not effective in identifying mechanisms of deregulation at multiple levels</p> Signup and view all the answers

    What is a challenge in performing clinical trials for kinase inhibitors?

    <p>Difficulty in obtaining compounds from different pharmaceutical companies</p> Signup and view all the answers

    What is a potential solution to overcoming resistance mechanisms in cancer treatment?

    <p>Using a multi-targeted drug</p> Signup and view all the answers

    What is a limitation of mass spectrometry-based approaches in identifying driver kinases?

    <p>They are not effective in identifying low abundant proteins</p> Signup and view all the answers

    What can occur if we do not fully understand the complexity of a given tumor type?

    <p>We may underestimate the complexity of the tumor type</p> Signup and view all the answers

    How many kinases were listed as primary targets in clinical testing in 2010?

    <p>About 50 kinases</p> Signup and view all the answers

    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.

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