Question 1

What is the most common EGFR mutation in lung cancer?

Accepted Answer

The two most common sensitising EGFR mutations in NSCLC are exon 19 deletions (del746-750 and similar variants, ~45% of all EGFR mutations) and the L858R point mutation in exon 21 (~40%). Together they account for approximately 85% of all clinically relevant EGFR alterations. Both stabilise the active kinase conformation and confer strong sensitivity to EGFR TKIs, with exon 19 deletions generally associated with slightly superior outcomes.

Question 2

How does T790M cause resistance to EGFR inhibitors?

Accepted Answer

T790M substitutes threonine at the gatekeeper position 790 with the bulkier methionine residue. This simultaneously increases ATP affinity approximately 100-fold through additional hydrophobic contacts with ATP's adenine ring, and sterically clashes with the hydroxyl-group-dependent binding pose of first and second-generation EGFR inhibitors (erlotinib, gefitinib, afatinib). The net result: kinase activity is fully restored despite saturating first-generation inhibitor concentrations. Osimertinib overcomes T790M by forming an irreversible covalent bond with Cys797, making competition with ATP irrelevant.

Question 3

Why do KRAS mutations cause EGFR inhibitor resistance?

Accepted Answer

KRAS lies immediately downstream of EGFR in the signalling cascade. Oncogenic KRAS mutations (G12C, G12D, G12V) lock KRAS in the GTP-bound active state, providing constitutive downstream RAF/MEK/ERK and PI3K/AKT signalling that is completely independent of upstream EGFR activity. When EGFR is inhibited in a KRAS-mutant tumour, the downstream pathway remains fully active — exactly as if EGFR were never engaged. This is why KRAS mutations mandate RAS testing before anti-EGFR antibody therapy in colorectal cancer and explain the ~3% of NSCLC EGFR inhibitor resistance cases attributed to KRAS.

Question 4

What drugs target EGFR mutations and how do they differ?

Accepted Answer

First-generation TKIs (erlotinib, gefitinib) are reversible ATP-competitive inhibitors that block the EGFR kinase domain competitively. Second-generation agents (afatinib, dacomitinib) form irreversible covalent bonds with Cys797 and additionally inhibit HER2 and HER4. Third-generation osimertinib forms an irreversible Cys797 bond with selectivity for mutant over wild-type EGFR, covering both activating mutations and T790M. Osimertinib is now the preferred first-line agent, achieving 18.9 months median PFS versus 10.2 months for first-generation TKIs in the FLAURA trial.

Question 5

What is EGFR signalling and why does it matter in cancer?

Accepted Answer

EGFR is a receptor tyrosine kinase that, upon ligand binding, activates two major oncogenic cascades: EGFR→GRB2→SOS→KRAS→BRAF→MEK→ERK (driving cyclin D1 and MYC for proliferation) and EGFR→GAB1→PI3K→PIP3→AKT→mTOR (driving BAD inactivation and protein synthesis for survival). In EGFR-mutant NSCLC, both cascades run constitutively without ligand — providing an unbroken signal for unrestrained tumour growth. The pathway's clinical importance stems from the high response rates to matched TKI therapy in the 15–50% of NSCLC patients carrying activating mutations.

Question 6

What happens after osimertinib resistance develops?

Accepted Answer

Resistance to osimertinib arises through diverse mechanisms detectable by liquid biopsy: C797S tertiary EGFR mutation (disrupts the covalent bond, ~20% of resistance), MET amplification (~15%), KRAS/BRAF mutations, RET fusions, and EGFR amplification. No single subsequent therapy is approved post-osimertinib failure. Strategies include platinum-based chemotherapy, EGFR-MET bispecific antibodies (amivantamab), and fourth-generation allosteric EGFR inhibitors (BLU-945, BBT-176) designed to overcome triple-mutant EGFR (del19/L858R + T790M + C797S).

Question 7

What is the difference between EGFR exon 19 deletion and L858R?

Accepted Answer

Both are sensitising mutations that constitutively activate EGFR kinase, but through different structural mechanisms. Exon 19 deletions remove the ELREA motif in the C-helix loop that normally contributes to autoinhibitory contacts, releasing the kinase from its resting state. L858R inserts arginine into the DFGφ activation loop motif, disrupting the 'molecular brake' that normally holds the loop in the inactive position. Both mutations are hypersensitive to EGFR TKIs, but exon 19 deletions are associated with slightly superior progression-free survival on osimertinib and may have different sensitivity to specific TKIs in head-to-head comparisons.

EGFR Gene Function

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