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Overcoming Resistance to Targeted Therapies in NSCLC - An Overview

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Targeted therapies have emerged as a promising approach in the clinical management of NSCLC. However, resistance to these therapies presents a formidable challenge.

Written by

Dr. Asma. N

Medically reviewed by

Dr. Kaushal Bhavsar

Published At November 23, 2023
Reviewed AtDecember 29, 2023

Introduction:

Non-small cell lung cancer is a condition in which cancer cells form in the lung tissue. The term "non-small cell" refers to larger cells compared to small cell lung cancer (SCLC) when viewed under a microscope. NSCLC is usually associated with exposure to smoke. Targeted therapy is a type of treatment that focuses on specific mutations and molecular abnormalities to inhibit the growth of cancer cells. The main targets include drugs that inhibit the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) present on the surface of cancer cells. However, a major challenge is the development of drug resistance. Therefore, ongoing research is dedicated to the development of new drugs.

What Is Resistance to Targeted Therapies?

Resistance to targeted therapies is a phenomenon where cancer cells, initially responsive to the targeted therapy, become less sensitive and eventually unresponsive to the treatment. This limits the long-term effectiveness of the therapy. There are two types of resistance:

1. Primary Resistance: This refers to the lack of initial response in a patient's cancer cells to the targeted therapy. It occurs when the patient does not show any response from the beginning. These cancers have inherent genetic alterations or characteristics. Primary resistance can happen due to tumor heterogeneity, pre-existing genetic mutations, or the presence of alternative signaling pathways. Primary resistance in targeted therapies includes:

  • Resistance to EGFR TKIs: This includes EGFR mutations, such as exon 20 insertions or duplications, which occur in approximately four percent of cases and are highly resistant to EGFR inhibitors. De novo EGFR T790M (threonine-to-methionine substitution within the gatekeeper residue at position 790) mutations are observed in about 1.5 percent of cases. Additionally, resistance can be attributed to secondary genetic alterations, such as the T790M mutation and MET (mesenchymal-epithelial transition) amplification, both of which can lead to intrinsic resistance.

  • Resistance to ALK Inhibitors: An ALK inhibitor, such as Crizotinib, is considered superior to chemotherapy; however, it may have side effects, such as gastrointestinal disorders and vision disorders. Primary resistance to ALK inhibitors can occur due to EML4-ALK (echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase) fusion variants.

2. Secondary Resistance: Also known as acquired resistance, this occurs when cancer cells are initially responsive to the therapy but develop resistance over time. Secondary resistance can occur due to genetic mutations, alterations in drug metabolism, epigenetic changes, or changes in the tumor's microenvironment. Secondary resistance in targeted therapies includes:

  • Resistance to EGFR TKIs: Resistance to targeted therapies can occur due to a mutation called T790M, which is found in approximately 50 percent of patients. This mutation arises due to the excessive use of adenosine triphosphate (ATP) as the primary source of cellular energy. Another mechanism leading to resistance involves bypass signaling pathways, which may arise in the case of PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutations and BRAF (B-Raf protein) mutations, leading to the activation of downstream PI3K/AKT signaling. Additionally, changes in tumor histology, such as transitioning from non-small cell cancer to small cell cancer or from epithelial to mesenchymal, can render the tumor less responsive to targeted therapies. These resistance mechanisms pose significant challenges in the effective treatment of certain cancers and warrant further research and the development of novel therapeutic strategies.

  • Resistance to ALK Inhibitors: Acquired resistance can occur due to two different mechanisms known as ALK dominant and ALK non-dominant. In the case of ALK dominant resistance, ALK is the primary factor contributing to the development of resistance. This can happen due to secondary mutations in the EML4-ALK fusion protein, which can interfere with the ability of Crizotinib to bind to the receptor. On the other hand, ALK non-dominant mechanisms involve other oncogenic mutations that lead to resistance. This accounts for approximately 20 percent of lung cancers. These alterations occur due to alternative downstream signaling pathways, such as mutations and amplifications.

What Are the Treatment Approaches Used to Overcome Resistance to EGFR TKIs?

The treatment approaches include:

  • TKI Continuation Beyond Progression: In cancer treatment, when the disease progresses, the treatment is typically stopped. However, in the case of EGFR-mutant cancers, discontinuing the treatment can worsen the disease. Therefore, in cases of isolated progression, local therapies are used in combination with targeted therapies. A clinical trial called ASPIRATION (a type of study involving lung cancer patients), which used first-line treatment Erlotinib, showed a delay in disease progression. However, more research is required in this area.

  • Chemotherapy Plus EGFR TKI: For patients with EGFR mutation-positive tumors, targeted therapy is continued along with platinum-based doublet chemotherapy. This approach is considered due to tumor heterogeneity and the suggested benefits it offers.

  • Third-Generation TKIs: This category includes inhibitors like AZD9291 and CO-1686, which can help overcome resistance developed by second and first-generation EGFR inhibitors. These third generation TKIs work by forming irreversible bonds with the EGFR, specifically targeting T790M mutations. Ongoing phase three trials show promising results and have the potential to establish a new treatment option.

What Are the Treatment Approaches Used to Overcome Resistance to ALK Inhibitors?

Treatment approaches for ALK inhibitors, such as Crizotinib, include the following:

1. Beyond Progression: In cases of limited progression, such as brain metastasis, local therapy is combined with continuing Crizotinib treatment. However, in the event of significant progression, the treatment is immediately switched to a second-generation ALK inhibitor, which has demonstrated high response rates.

2. Next-Generation ALK Inhibitors: Second-generation ALK TKIs have shown promising results and include the following:

  • Ceritinib: A small molecule targeted therapy that blocks the ALK protein. It is more than 20 times more potent than Crizotinib. Ceritinib has shown promise in cases of patients who are new to ALK inhibitors or have previously received Crizotinib. However, it has higher side effects, such as vomiting and diarrhea, compared to Crizotinib.

  • Alectinib: A powerful and selective ALK inhibitor, stronger than Crizotinib. Alectinib has demonstrated good effectiveness in cases of patients who are new to ALK inhibitors or have previously received Crizotinib. It has also shown positive results in cases of brain metastasis (tumor spreads to the brain). Ongoing phase two and three trials have demonstrated promising outcomes.

  • AP26113 and Other Novel ALK Inhibitors: Several other drugs, such as AP26113, TSR-011, RXDX-101, CEP-37440, etc., have been developed and have shown effectiveness in cases of brain metastasis. AP26113 is active against many mutations, including the T790M mutation. These new inhibitors show promising results in improving treatment outcomes.

Conclusion:

Targeted therapy is a major advancement in cancer treatment, but ongoing research and clinical trials are necessary to address the challenge of resistance. The first- and second-generation EGFR and ALK inhibitors have demonstrated successful outcomes in cases of ALK rearrangements and EGFR mutations. However, resistance to these therapies often develops within a year of treatment, posing a significant challenge. To overcome this resistance, third-generation EGFR inhibitors have been developed and are currently undergoing phase 2 and 3 trials. These novel inhibitors have shown promising outcomes in effectively tackling resistance and improving treatment efficacy.

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Dr. Kaushal Bhavsar
Dr. Kaushal Bhavsar

Pulmonology (Asthma Doctors)

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