Related Experiment Video

Updated: Jun 3, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors

Lecia V Sequist1, Belinda A Waltman, Dora Dias-Santagata

  • 1Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. lvsequist@partners.org

Science Translational Medicine
|March 25, 2011
PubMed

Insights

Drug resistance to epidermal growth factor receptor (EGFR) inhibitors in lung cancer can emerge through various genetic changes, including transformation to small cell lung cancer (SCLC). Some resistance mechanisms are reversible, allowing for re-treatment with EGFR inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Lung cancers with epidermal growth factor receptor (EGFR) mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs).
  • Acquired drug resistance is a significant clinical challenge in treating these cancers.

Purpose of the Study:

  • To investigate the diverse mechanisms of acquired resistance to EGFR TKIs in non-small cell lung cancer (NSCLC) with EGFR mutations.
  • To identify potential therapeutic strategies for overcoming acquired resistance.

Main Methods:

  • Systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant EGFR-mutated NSCLC.
  • Evaluation of known and novel resistance mechanisms, including genetic alterations and histological transformation.
  • Assessment of tumor sensitivity to EGFR inhibitors and standard treatments for small cell lung cancer (SCLC).

Main Results:

  • All resistant tumors retained original EGFR mutations; some acquired known resistance mechanisms (e.g., T790M, MET amplification).
  • Unexpected changes included EGFR amplification, PIK3CA mutations, and epithelial-to-mesenchymal transition.
  • Notably, 14% of resistant tumors transformed into SCLC, which responded to SCLC treatments.
  • Reversible resistance mechanisms were observed, with sensitivity restored upon cessation of EGFR inhibitor treatment.

Conclusions:

  • Acquired resistance to EGFR TKIs in NSCLC is multifactorial, involving genetic alterations and histological transformation.
  • Transformation to SCLC represents a distinct resistance mechanism with therapeutic implications.
  • The dynamic nature of resistance suggests that serial monitoring and re-assessment of cancer throughout treatment are crucial for optimizing patient management.

More Related Videos

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
Tumor Progression02:07

Tumor Progression

Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...