PATHWAYS to CANCEREman El-AttarMsc, MD, CPHQ

Lecturer of Chemical PathologyMedical Research Institute 2014

Cellular Signalling Pathway

• Cells receive information from many different growth

factor receptors and from cell-matrix and cell-cell contacts.

• Cellular signaling pathways are not isolated from each

other but are interconnected to form complex signaling

networks

• They must then integrate this information to regulate

diverse processes, such as protein synthesis and cell

growth, motility, cell architecture and polarity,

differentiation, and programmed cell death.

Cellular Signalling Pathway

• The same signaling molecules are used to control different processes within different signaling complexes or at different intracellular locations.

• Moreover, signaling pathways could generate different outcomes in different cell types.

• The intricacy of cellular signaling networks has major implications on our understanding of tumor cell behavior and our ability to use this knowledge for cancer therapy

Most Common Signaling Pathways

But actually the big picture much more complicated, interconnected and looks more like this !!

Nature Reviews designed the network as a Subway map; stops & lines leading to main stations

Subway map designed by Claudia Bentley.Web design by Nick Allin.Edited by Cath Brooksbank and Sandra Clark.© 2002 Nature Publishing Group.

Cell Cycle

Two classes of regulatory proteins:

1) Cyclins: 2) Cyclin Dependant Kinases (CDKs)

Signalling pathways

• Mutations in components of signaling pathways that control cell growth underlie tumour initiation

• Ras, PI(3)K and mTOR are 3 signaling pathways that form an intersecting biochemical network. When mutated, these drive unrestricted cell growth.

• Ultimately, these pathways drive tumorigenesis through the coordinated phosphorylation of proteins that directly regulate protein synthesis, cell-cycle progression and metabolism, and of transcription factors that regulate expression of genes involved in these processes

The Ras pathway

• The name 'Ras' is an abbreviation of 'Rat sarcoma'

• RAS is a family of GTPases that are activated by a wide range of cell-surface molecules

• 3 isoforms : KRAS, NRAS, HRAS

The Ras pathway

Evading apoptosis Proliferation

The importance of this pathway is that multiple signals are funneled into MEK and ERK kinases (this pathway), allowing a nodal point for therapeutic targeting.It is is like a bottle neck where therapy can be targetted

The Ras/RAF/MAP kinase pathway

• Upstream components of the pathway, such as the RAS and RAF are potent oncogenes. In cooperation with other events, can lead to profound changes , transforming normal cells into fully malignant .

• Components of this pathway are under intense investigation as possible targets for anti-cancer therapeutics.

• Mutated Ras is associated with 20−30% of all human ∼cancers are often not responsive to established therapies

• Resulting in a staggering 3 million new cancers diagnosed worldwide each year with RAS mutations.

RAS mutations

• In particular, K-Ras, the most frequently mutated Ras isoform, is considered one of the most important but 'undruggable' targets in cancer research.

• Despite intense efforts in pharmaceutical industry and academia, a therapeutic grip on oncogenic Ras proteins has remained elusive.

RAS mutations• Described in both hematologic and solid-tumor malignancies.• Different cancers (based on cell type of origin) show a propensity

to mutate different RAS isoforms. – KRAS is the dominantly mutated isoform in colorectal and lung cancers– NRAS mutations dominate in hematologic malignancies and melanoma

• Cancers with the most frequent RAS mutations are pancreatic cancer (90%), colorectal cancer (40%), non–small cell lung cancer (30%), bladder cancer (30%), peritoneal cancer (30%), cholangiocarcinoma (25%), and melanoma (15%).

• In contrast, lymphomas, acute lymphoblastic leukemia, hepatocellular carcinoma, osteosarcoma, and prostate cancer less commonly contain RAS mutations.

RAF mutations

• RAF kinases have 3 isoforms: BRAF, CRAF, ARAF

• Identifying mutations in BRAF in human cancer has opened up profound new therapeutic opportunities for the management of cancer.

• 6% of human cancers contain activating mutations in BRAF that result in more than 500,000 new cases of BRAF-mutated cancer diagnosed worldwide each year.

• Similar to RAS mutations, BRAF mutations are profoundly oncogenic in cooperation with other genetic events and are capable of fully transforming normal cells.

BRAF mutations• The most common mutation in BRAF by far is the substitution of

valine 600 by glutamic acid (V600E), which accounts for– more than 85% of the BRAF mutations in melanoma,

– more than 50% of the mutations in non-small cell lung cancer

– more than 95% of mutations in colorectal cancer, cholangiocarcinoma, and hairy-cell leukemia.

• Just as RAS-mutated cells, BRAF mutation, are dependent on MEK and, by inference, ERK signaling for cell survival and proliferation.

• MEK inhibitor: trametinib or dacarbazine (downstream)

• BRAF inhibitors: vemurafenib, dabrafenib (upstream)

• LGX818 F

PI3K/AKT/mTOR pathway

• The PI3K/AKT/MTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer(e.g. breast cancer and non-small-cell lung cancer) and longevity.

• The PI3K/AKT/MTOR pathway is activated by IGF1 and has a number of downstream effects which either promote protein synthesis or inhibit protein breakdown.

• In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation.

• Cancer drugs trials aim to inhibit this signalling sequence at some point.

Combination of PI3K and MEK inhibitory drugs (in purple) to block the growth of lung tumors in a RAS-driven mouse transgenic mode Nature Medicine 14, 1315 - 1316 (2008)

mTOR

• Mammalian Target of Rapamycin• Two distinct and mutually exclusive TOR complexes:– Raptor (the mTORC1 complex) : strongly inhibited by

rapamycin (main focus of research)– Rictor (mTORC2)

• Growth factors signal to mTORC1 complexes through both PI3(K)-AKT & Ras-ERK pathway.

• Low nutrient availability (for example, low glucose or hypoxia) inhibits mTORC1

PI3K/AKT/mTOR pathway

PI3 K

: mutationally activated in cancer

: mutationally inhibited in cancer

Red

Green

: mutationally activated in cancer

: mutationally inhibited in cancer

Cell growth, Gycolysis and Angiogenesis

Red

Green

• These findings have strong implications for cancer therapeutic strategies.

• Rapamycin-based mTOR inhibitors• Inhibitors of PI(3)K–AKT signaling• Prolonged use of an inhibitor of a certain

pathway (e.g. Rapamycin) could lead to enhanced activation of another pathway (PI3K). Thus combinations of drugs may be useful to avoid bypass routes

THANK YOUEman