Download Catenin Mutations in Cancer

Contextual Contributions of Oncogenic and Tumor
Suppressive Pathways:
- Our Opportunities and Challenges in Therapeutic Development -
Dr. Qun Lu
Leo Jenkins Cancer Center at BSOM
UNC Lineberger Comprehensive Cancer Center
Our Progresses in The Past Four Decades
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Remarkable Treatment Successes
 Cytotoxic chemotherapy drugs such as Cisplatin
Before cisplatin was available, metastatic testicular cancer had a mortality rate of 95%.
Cisplatin based regimens resulted in a 60% cure rate for this disease.
 Target specific drugs such as Gleevec and Iressa
By specifically blocking the abnormal protein called BCR-ABL, Gleevec kills the
leukemia cells. By inhibiting tyrosine kinase activity of EGFR, Iressa suppresses NSCLC.
Billions of dollars have been invested on R&D, why are
we still so far away from conquering cancer?
 What are the modern
strategies for drug discovery
against cancer?
Most strategies for cancer drug
discovery focus on attacking specific elements
of a given biological pathway of cancer cells to
achieve target specificity with minimized
toxicity. This approach, although with long term
merits, has not produced the desired numbers of
viable drugs because most such leads succeeded
in vitro or in animal studies do not show the
same efficacy in human trials. Consequently,
few viable cancer drugs enter markets in recent
years leading to skyrocketed R&D cost.
Dichotomy of Oncogenes and Tumor Suppressors
Challenges Anti-cancer Therapies
(2009)
(2010)
(2010)
Surprising Discoveries in Cancer Research
 Oncogenic Versus Tumor Suppressive Signaling Pathways
When oncogenes were identified, we thought that we have
found the bad guys. So the theory was that if we inhibit the
functions of oncogenes, we can stop the disease. It was also
thought that since there are tumor suppressors, we can increase the
function of the tumor suppressors to inhibit the disease
progression.
However: Many genes and many signaling pathways can
be oncogenic in one context, but be tumor suppressive at a
different context or at different stages.
Myc-pRb-E2F axis
Myc oncogene expression is deregulated in 15 to 30 % of human cancers,
resulting in elevated levels of Myc protein.
 As mitogenic promoter: Myc perturbs the decision to phosphorylate
tumor suppressor pRb and thereby alter cell cycle progression.
 As pro-apoptotic factor: Myc induces cell to undergo apoptosis unless
they have been protected from apoptosis by some other, previously acquired
anti-apoptotic allele (e.g., a ras oncogene).
In the presence of the anti-apoptotic mutation, the strong mitogenic effects of
the myc oncogene then become apparent.
 As proliferation promoter: both Myc and Ras can activate E2F
transcription factor, which can initiate cell proliferation.
 As pro-apoptotic factor: both Myc and Ras can also activate E2F
transcription factor, which can initiate cell death.
Indeed, the oncogenic roles of E2F could be context-dependent.
Zhang et al., 2010. Future Oncology
TGF 1 signaling axis
 As a tumor suppressor: for most normal epithelial cells and at the early stages
of tumor development. This process occurs largely through the activation of TGF 1
receptor complex and phosphorylation of Smads and other signaling pathways.
 As metastasis promoter: elevated expression of TGF 1 may enhance malignant
properties of tumor cells through effects on cell invasion, metastasis, epithelial to
mesenchymal transition (EMT), or anti-tumor immunity. This alteration in functions
of TGF 1 in cancer development is likely due to its interaction with other signaling
pathways such as ras oncogene that becomes activated during tumor progression.
Phosphatidylinositol 3-kinases (PI3Ks) signaling axis
 Oncogenic functions of PI3K: In cell-based assays, PIK3CA mutations confer
a gain of function as measured by lipid kinase activity, constitutive activation of
Akt, and cellular transformation. Therefore, the frequency of PIK3CA mutation is
consistent with the significance of PI3Ks in breast cancer pathogenesis.
 Positive prognostic significance of PIK3CA mutations: Some studies
indicate that PIK3CA can even be a “good” activating mutation in cancer. This is
clinically relevant, because it could significantly affect the design of clinical trials
planned for PI3K-targeted therapy.
Zhang et al., 2010. Future Oncology
The Armadillo/β-catenin superfamily
Armadillo
β-Catenin
-Catenin
p120-catenin
ARVCF
p0071
-Catenin
843 aa
781 aa
745 aa
968 aa
962 aa
1211 aa
DSWV
1225 aa
-Catenin in comparison to other armadillo domain containing proteins
Incompatible Observations
on Human tissues and Cultured Cell Lines
- Make drug discovery more challenging
Cancer
Esophagus
食管
Breast
乳腺
Benign
Prostate
前列腺
Lung
Lu et al., 2005
(180 cases TMA)
Zhang et al., 2010
135 cases NSCLC
Promoter Mutations Can Increase -Catenin Expression
in Prostate Cancer (PCa) Cells
Wang et al., 2009. Oncogene
In Culture, -Catenin Expression Is Moderate
But Its Expression Increases PCa Cell Viability
and Tumor Xenograft Growth
Zeng et al., 2009. Mole Cancer
However, -Catenin Also Displays Tumor Suppressive Activities
HMEC Cells
MDCK Cells
PCa Cells
Lu et al., 1999; J. Cell Biol
Westbrook et al., 2005; Cell
Zeng and Lu, unpublished
So, Why Does -Catenin Display Opposite Functions ?
Does Its Mutations Play a Role in PCa Cell Fate and Behavior?
-Identification of -Catenin Mutations in Cancer-
Nopparat and Zhang et al., 2015. Oncogene
Identification of Functional -Catenin Mutations
in Human Prostate Cancer
1225 aa
-Catenin
811, 816
1027. 1095, 1096
1142
 Mutations occur at
very high frequency;
 Mutations occur in
other cancer types as
well;
 May affect -catenin
functions.
Patent pending
Majority of Cancer Associated Mutations Are Limited
to the Carboxyl Half of -Catenin
No-sense or Missense Mutations:
Prostate cancer:
K811N, K811Q, K1027Q, S1095S
(Primary tumor)
Deletion or insertion:
Prostate cancer:
K816R, N1096R, S1140Q
Between exon 21 and 22—EGFR
(Primary tumor)
Ovary cancer: P1218L
(Primary tumor)
Large intestine: Y1128fs*6
(Culture sample)
Large intestine: P1159S
(Culture sample)
NSCLC: K703R
(Culture sample)
Pancreas cancer: A685V
(Culture sample)
Skin cancer: F1172F
(Culture sample)
Mutations Can Alter -Catenin Localization in Cells
811, 816
Lu et al., 1999
Differential -Catenin Localization May be Driven by
Mutations in Prostatic Tumors
Zhang and Lu, unpublished
Some -Catenin Mutations May Lead to Gain-ofFunctions in Cell Proliferation/Survival, Adhesion, and
Energy Metabolism
Compound Transgenic Mice Expressing
Both Oncogenic Myc and δ-Catenin Mutation
Contextual Contributions of Oncogenic and Tumor
Suppressive Pathways
Acknowledgements
The Lu Lab
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Amy Friesland
Joyce Zhang
Christi Boykin
Jian-Ping Lu
Tao Wang
Yan Zeng
Kwonseop Kim
Sarah James
Sonja Bareiss
Collaborators
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Yan-hua Chen
Lei Ding
Huchen Zhou
Robert Matusik
Scott Shappell
Frank Longo
Baoan Chen
Xuemei Wang