Cancer Hallmark #1: Unstoppable Cell Growth

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Cancer Hallmark #1: Unstoppable Cell Growth

As previously mentioned, upon activation by EGF binding, EGFR transduces growth signaling downstream. Under normal conditions, EGFR is only able to transduce signal when it is activated by external stimuli such as EGF.
Under cancerous conditions, however, EGFR mutations enable EGFR to stay activated all the time in the absence of external stimuli (a phenomenon also termed as "constitutive activation"). As a result, EGFR propagates growth signals continuously to downstream components, leading to continuous cell cycle progression and hence uncontrolled cell growth. This fact explains why EGFR is an attractive therapeutic drug target. A few examples of FDA-approved EGFR inhibitors include:
  • Afatinib (for Non-small cell lung cancer, NSCLC)
  • Erlotinib (for NSCLC)
  • Gefitinib (for NSCLC)
The EGF/EGFR signaling is just one example of how cumulative mutations associated with cell growth pathways enable constant cell cycle progression, cell division, and cell proliferation in the absence of growth factor stimulation. In cancer, invariably, multiple pathways become constitutively activated simultaneously, which is also the reason why cancer cure remains a daunting challenge. The same observation also provides a compelling rationale for combinatorial chemotherapeutic strategies by targeting more than one signaling pathway - a topic discussed in more detail in the latter portion of this course.
Rarely is nature so uncomplicated. Several EGFR family members have been identified, including EGFR1, EGFR2, EGFR3, and EGFR4. EGFRs can form dimers and the above-described three drugs target different EGFR family members, illustrated in the simplified diagram as follows: