20 crucial facts on KRAS targeted therapy for lung cancer

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KRAS targeted therapy for lung cancer treatment; will it be the next success?

Among 20%-25% lung cancer patients have at least some form of KRAS (Kirsten rat sarcoma viral oncogene homolog) gene mutation. This accounts for a huge burden of cancer deaths. Previously, targeting KRAS mutation and KRAS signalling pathways in targeted therapy was a failed attempt. It was an untargetable target. However thanks to continuous scientific studies, KRAS targeted therapy for lung cancer has become a successful treatment. Surprisingly, the FDA has approved the first KRAS targeted therapy for lung cancer patients recently. This is an interesting and ongoing journey towards finding new treatments for a better improvement for cancer patients.

In this article, you will get to know full coverage about KRAS targeted therapy for lung cancer.

1. What is the current status of KRAS targeted therapy for lung cancer treatment?

Despite having a dark past, KRAS targeted therapy for lung cancer is adding significant value to cancer therapy. Most importantly, KRAS mutation is a major oncogene that leads to cancer progression. Although KRAS mutation is such a main target in lung cancer, previous treatments against the KRAS mutant gene were not a success. This is because the KRAS gene lacks specific binding pockets for small molecule inhibitors. To clarify, those small molecules are the targeted drugs. In other words, targeted drugs are designer drugs to specifically target KRAS mutated genes. Thus, it was an “undruggable” or “untargetable” target.

However, novel genetic identifications and diverse analysis methods, certain treatments against KRAS gene mutated lung cancer have shown up recently. RAS signalling towards the tumour growth, we focus on KRAS which is the most frequently mutated RAS isoform. For instance, KRAS G12C inhibitors for example AMG 510 and MRTX 849 are becoming effective in both preclinical and clinical treatments. In addition, combination products such as targeted therapy with immune checkpoint inhibitors, KRAS downstream inhibitors, or direct covalent inhibitors have also shown them as effective drug therapies. Those combination products focus on lung adenocarcinoma (LADC) patients and all lung cancer patients in personalized treatment plans.

Overall, the novel KRAS mutation-targeted drugs are currently under development and introduced at present. Advanced technologies and scientific research on the current status push researchers towards it. The improvement of KRAS targeted therapy for lung cancer is a new step of targeted therapy. Along with the personalized medication plans for lung cancer patients, mutated KRAS gene-targeting therapies are becoming effective.

2. What is the KRAS protein?

KRAS or Kirsten Rat Sarcoma viral oncogene homolog is a type of gene that helps cancer growth. In contrast, in normal cells, the KRAS gene provides the directions to make a protein called K-RAS. Moreover, it is a part of the RAS/MAPK signalling pathway which is a cell signalling pathway.

KRAS is a member of small GTP (Guanosine triphosphate) binding proteins. The family is the RAS superfamily. It has five subfamilies categorized based on structure, function, and sequence. They are,

  • RAS
  • RHO
  • RAN
  • RAB
  • ARF GTPases

In addition, the RAS subtype has more than six families which are,

  • RAS
  • RAL
  • RAP
  • RHEB
  • RAD
  • RIT

KRAS protein has four domains. A domain is a functional or structural unit in a protein. The G domain of the KRAS protein contains the GTP binding pocket. It is a region that is essential to the connection between GTPase activating proteins.

3. What are the functions of the KRAS protein in normal cells?

The KRAS protein carries signals to the cell nucleus from outside. These signals provide the instructions to the cells to grow, divide, mature, function, and change or adapt (differentiation). The KRAS protein is a GTPase. In other words, it changes when a molecule called GTP binds to it. KRAS protein acts as a switch, it converts from inactive form to active form when bound with GDP (Guanosine Diphosphate) and GTP respectively.

To clarify, when the protein binds with GTP it switches to its active form. This form can transmit signals to the cell nucleus. On the other hand, binding with GDP deactivates the protein and that form cannot rely on those signals.

In normal physiological conditions, Guanine Nucleotide Exchange Factors (GEFs), or GTPase-activating proteins. Those factors help the KRAS protein to switch between two forms.

Usually, KRAS binds with GDP in normal conditions. When binding with GTP the protein structure changes and makes two results.

  1. Affect the KRAS and GAPs and this increases the activity of the GTPase system of the RAS protein.
  2. Affect the interaction with GEFs and help to release the bound GTP.

Moreover, the KRAS gene is a type of oncogene. The speciality of oncogenes is in its mutated statues it supports the normal healthy cells to become cancerous cells.

4. How does the KRAS protein signalling happen?

KRAS is a major cell signaling regulator in cells. It coordinates the transduction signals from the outside to the cell nucleus. The signals are essential in,

  • Cell differentiation
  • Cellular growth
  • Chemotaxis
  • Apoptosis – programmed cell death.

This means after damage or after their lifetime the normal cells die. That process is Apoptosis.

The signal transduction of KRAS protein does not happen in the cell membrane. In addition, the KRAS protein can trigger the downstream signal pathways. For that purpose, signals from the other cell compartments such as the endoplasmic reticulum, and Golgi apparatus are in the main role.

The signals from the outside of the cells stimulate the conversion of deactivated KRAS-GDP form into activated KRAS-GTP form. This triggers the activation of several other signaling pathways. For instance,

  • Mitogen-activated protein kinase pathway (MAPK)
  • Phosphoinositide 3 kinase pathway (MI3K)
  • Ral-GEFs pathway.

Collectively, these signal pathways do work on carrying necessary signals to the cell nucleus. Ultimately, those signals progress the cellular functions and growth mechanisms.

Cellular signaling pathway of RAS proteins in normal cells.
Figure No.01: Cellular signaling pathway of RAS proteins in normal cells.

Markedly, if the basic gene or KRAS gene is mutated, then the whole process goes the wrong way. This helps more to make cancer cells develop instead of building normal cells.

Blocking the major pathways is another main focus on the KRAS targeted therapy for lung cancer. Certain drugs can attack those signaling pathways which provide instructions for lung cancer. Using such drugs in KRAS targeted therapy for lung cancer makes the treatment a more personalized plan for a particular patient.

5. What do you mean by KRAS gene mutation?

Genes in the RAS family easily get mutations. Among them, KRAS is in the first place. In addition, HRAS and NRAS are other types of mutations. 86% of RAS gene mutations are KRAS mutations. KRAS mutation is more common in lung adenocarcinoma. NSCLC patients are the first type of lung cancer and about 16% – 40% of samples analyzed have positive KRAS gene mutation.

There are main codons in which possible gene mutations can happen. Frequently, 12, 13, and rarely at codons can get the mutation. Moreover, codons 63, 117, 146, and 119 are also other genes that can undergo mutation. According to the amino acid mutation which happens, there are different types of KRAS mutations. For instance,

  • KRAS G12A
  • KRAS G12V
  • KRAS G12D
  • KRAS G12C.
lung cancer
Figure No.02: the main gene mutations in RAS isoforms in different cancers

This data from the publication of Acta Pharmaceutica Sinica B.

As smoking increases the risk of lung cancer KRAS mutation is more common among smokers than non-smokers. There are nucleotide transversions in these mutations. Nucleotide transversion is a kind of point mutation in which one nucleotide changes with another. The most common types of KRAS mutations in NSCLC patients are G12C (~40%) and G12V (~22%). These arise from G/T transversions.

Various types of mutations have different features. For example, G12D variation in NSCLC can be treated better than the G12C or G12V variations. Similarly, these variations provide information about the disease’s aggressiveness and its sensitivity to medications. In the development of KRAS targeted therapy for lung cancer, experts identified the value of targeting specific KRAS mutations.

Percentages of different types of KRAS gene mutations in lung adenocarcinoma (LADC) patients
Figure No.03: Percentages of different types of KRAS gene mutations in lung adenocarcinoma (LADC) patients

This data is available in the publication “Current therapy of KRAS mutant lung cancer” in 2020.

After all, wild-type KRAS and KRAS mutations have an association. This connection has proved that it can increase cancer progression. The wild-type KRAS promotes the KRAS mutant lung cancer development. In other words, it helps the KRAS mutation to make cancer cells.

6. What is the KRAS G12C mutation in lung cancer?

KRAS mutation G12C is a point mutation. To clarify, at the position of the 12th codon, the amino acid Glycine is replaced by Cysteine. This is the most common type among the KRAS variants in lung cancer. The mutation causes oncogene KRAS to progress towards cancer cell development. In other words, the substitution of Cysteine from Glycine makes the gene more suitable as a helper for cancer cell growth.

Although the distribution of mutations of the RAS family is not uniform, the KRAS isoform responsible for about 86% of cancer patients. The KRAS mutation presents 30% in adenocarcinoma patients in Western countries and 10%-15% cases in Asian countries. These data from the publication in the International Journal of Molecular Sciences. Among the above communities, the KRAS G12C variant is more popular in patients with lung adenocarcinoma. It is 13% of all lung adenocarcinoma patients. Moreover KRAS G12C mutation present in overall cancer patients more than 50%.

Advanced techniques can identify the exact location of the mutant Cysteine of KRAS G12C. That mutant location is located near the narrow pocket of the inactive form of the KRAS protein. Similarly, GDP bound form of the KRAS protein. This special location allows the drugs in KRAS targeted therapy for lung cancer, selectively attack the mutant Cysteine amino acid. The drug binds with the mutant Cysteine by a covalent bond. In addition, there is a groove or a canal near the Histidine 95 (H95) of the KRAS protein. This canal provides an additional site for stabilizing the binding of inhibitors.

In summary, with the advancement of scientific research KRAS G12C mutation is identified as an ideal match for KRAS targeted therapy for lung cancer.

7. What is the KRAS G12A mutation in lung cancer?

Similarly, the KRAS G12A mutation is a point mutation. The amino acid Glycine is replaced by the amino acid Alanine. The KRAS protein has 189 amino acids. The point mutation happens at the 12th amino acid.

Other than lung adenocarcinoma, KRAS G12A mutation presents in,

  • Colon adenocarcinoma
  • Colorectal adenocarcinoma
  • Endometrial adenocarcinoma
  • Rectal adenocarcinoma

The KRAS G12A mutation serves as a useful biomarker in KRAS targeted therapy in lung cancer. Various drugs used in targeted therapy like gefitinib, afatinib, erlotinib can attack the mutation successfully. Several clinical trials are ongoing to evaluate the effectiveness of the target molecules.

8. Can you get the KRAS mutation inherently?

The KRAS gene mutation is a somatic mutation. In other words, people get the mutation during their lifetime due to different reasons. People do not get somatic mutations by their family members to clarify you cannot get the KRAS gene mutation inherently.

9. What is the KRAS G12V mutation?

In the KRAS G12V mutation, at the 12th position, Valine presents instead of Glycine. KRAS G12V mutations also mostly occur in persons with a smoking history.

10. What is the KRAS G12D mutation?

As previously, KRAS G12D is a point mutation. In the 12th position of the amino acid chain, there is an aspartic acid molecule (aspartic acid is named as “D”) instead of Glycine. But this mutation is not common among lung cancer patients.

11. What is the basis of Kras targeted therapy for lung cancer?

What is targeted therapy?

Targeted therapy is a novel treatment of cancer therapy. Molecules target specific genes or proteins which provide support for the cancer cells. In other words, genes, and proteins protect cancer cells to avoid normal cellular damage mechanisms and survive freely.

 This is a very effective method in cancer treatment in various aspects. Most oncologists worldwide recommend targeted therapy as first-line treatment and also with other common therapies as well. For example chemotherapy, radiation, and surgery.

How to combine the KRAS gene with targeted therapy in lung cancer?

Although KRAS mutation was an undruggable target previously, many researchers have found successful pathways against it. The structure of KRAS protein is slightly different from other proteins, in other words, the KRAS has a thin and smooth protein structure and its grooves are not suitable for the targeted molecules to bind with. Being the most mutated gene in human cancers KRAS provides a wide selection and research to find the most appropriate methods.

The KRAS mutation’s molecular structure and its diversity allow the drugs to target it effectively. Based on current studies drugs used in the KRAS targeted therapy for lung cancer.

In lung cancer, especially in NSCLC, there are different possible pathways that the targeted drugs can attack. Since the KRAS mutation reaching seems not possible, focus on other pathways was high. As a result, targeting KRAS signaling pathways come to the audience. Signaling pathways in the RAS specially MAPK, PI3K pathways.

12. Why KRAS targeted therapy for lung cancer previously unsuccessful? Previous efforts

Due to some blockages from KRAS protein, the previous efforts for KRAS targeted therapy for lung cancer were not a success. For instance,

  • The KRAS protein binds with GTP with a very strong connection in its active form. Inhibiting those strong bonds needs a potent inhibitor drug. Traditional inhibitors cannot break such a strong bond.
  • Clear pockets for small molecules to bind with the KRAS protein are not available. Since the targeted drugs are small molecules and they cannot effectively bind to the KRAS protein to inhibit it.

Therefore, the focus went to other alternative paths. For instance, blocking the KRAS inhibiting association, identifying artificial inhibitors, etc.

Blocking KRAS membrane association

KRAS protein needs to attach to the cell membrane for its activation. Once the KRAS proteins develop inside the cell it prepares them as suitable to attach to the cell membrane. They become more lipid-loving structures because the cell membrane has lipids. Farnesyltransferase enzymes help this process. The enzyme farnesyltransferase inhibition was one of the failures in targeting mutant RAS. Tipifarnib and Lonafarnib are the first drugs that worked as farnesyltransferase enzyme inhibitors.

This did not show good clinical efficacy with advanced Non-Small Cell Lung Cancer (NSCLC). This happened because the enzyme is very tricky, it has another pathway of doing the activity using another enzyme called geranylgeranyltransferase I (GGTase I).

It easily overcomes the effect of the drug.

However, inhibition of both enzymes did not show any positive outcomes. Due to the non-selectivity of the drugs, successful selection for this approach was not a success. The drugs used could bind with a wide variety of receptors so the desired outcome of just stopping the specific enzyme activity was not there.

Synthetic lethality partners

The Synthetic lethality approach in KRAS targeted therapy for lung cancer focuses on the targets of special types of cells. Those are the cells bearing activated KRAS oncogene. Several drug screens and cell-line screen methods are used to identify unique cells with KRAS mutation but not wild-type cells. Their results are then classified into different categories.

  • Cell cycle and mitosis
  • Polo-like kinase 1
  • Anaphase promoting complex
  • Cell survival
  • Transcriptional programs
  • B-cell lymphoma extra large
  • Snail family transcriptional repressor 2 (SNAIL 2)
  • Growth and survival signals.

Unfortunately, after putting these efforts several obstacles blocked the plan. For instance,

  • Highly complex genetic structures and functions of KRAS mutated cells
  • Blocks of experimental processes ( inconsistency in methodology, selection of cell lines )
  • Less ability of synthetic lethality drugs
  • Lack of validity

Another interesting synthetic lethality agent is the inhibition of discoidin domain receptor 1 (DDR1) and NOTCH signaling together. This has shown a much greater clinical effect than traditional chemotherapy.

Despite having advanced methods of synthetic lethality partners it is still not a successful treatment for KRAS positive NSCLC patients.

KRAS targeted therapy using downstream effectors of KRAS signalling pathways

Many downstream pathways involved in KRAS signals are useful targets. Drugs that can attack and block those pathways may match as targeted therapies in KRAS targeted therapy for lung cancer. The main downstream pathways are

  • RAF
  • MEK
  • PI3K
  • mTOR

RAF inhibitors

Dabrafenib and vemurafenib are two 1 B-RAF inhibiting drugs. Both of these drugs are effective in targeting B-RAF mutant lung cancer. However, there is less benefit in the treatment of patients with KRAS mutation. The reason is the C-RAF is the gene that regulates oncogenic signaling. Some studies say two of these drugs are not suitable for KRAS mutant lung cancer because they can increase tumour growth and development. They bind to the B-RAF and that is the reason for tumour growth. This is the “MAPK paradox”.

MEK inhibitors

Based on the genetic studies several MEK inhibitors are in clinical trials and under development. Most of these drugs are allosteric kinase inhibitors. The MEK inhibiting drugs are special because they have high specificity to the target. They bind to specific receptors on MEK but not to other non-target sites. Thus less toxic.

Selumetinib and Erlotinib are two MEK inhibitors that were in phase 2 clinical trials. But they failed to show any positive response over normal monotherapy in KRAS mutant and KRAS wild type advanced NSCLC patients. Moreover, combination therapy resulted in toxicities and needed to stop the medication.

Other downstream pathway inhibitors

Drugs that can inhibit the following pathways are downstream pathway inhibitors.

  • PI3K
  • AKT
  • mTOR

These are signaling pathways responsible for oncogenic KRAS signals. Inhibiting the PI3K activation prevents the KRAS mutated lung cancer or tumour progression. Various drugs in phase 1 clinical trials under the evaluation of their efficacy of successful inhibition. They investigate the efficacy of targeting PI3K/AKT/mTOR pathways including MEK inhibitors. Patients with advanced-stage solid tumours including NSCLC belong to the study.

  • In phase 2 clinical trials mTOR inhibitor ridaforolimus showed little clinical benefit in NSCLC patients but only a middle-low improvement in progression-free survival (PFS).
  • Defactinib is a non-receptor focal adhesion kinase (FAK) inhibitor drug. This drug also failed to show any improvement in NSCLC patients in phase 2 clinical trials.
  • Panaxynol was another drug that failed to improve clinical signs. Since patients show high resistance to Panaxynol was the reason behind this failure. Panaxynol is a heat shock protein (HSP90) inhibitor. HSP90 inhibitors in KRAS mutant NSCLC patients were thought to be a great target in KRAS targeted therapy for lung cancer.

13. What are the drugs in development for KRAS targeted therapy for lung cancer?

Despite the failures of different efforts of KRAS targeted therapy for lung cancer, novel drugs continuously come up in the practice. Improvement of modern technologies and novel drug development push researchers to put their focus on targeting not only KRAS mutation but also specific mutant alleles.

As a result, they have come up with different alternative pathways to attack the gene/protein and signaling pathways.

Covalent KRAS inhibitors

  • AMG 510

This is a novel drug. AMG 510 is a small molecule drug that can bind to the amino acid cysteine in the KRAS G12C mutant protein by a covalent bond. Therefore it blocks the KRAS protein in its inactive form or KRAS-GDP form. Hence, help to the cancer cells from the protein is blocked. This reduces cancer growth. Furthermore, AMG 510 can improve the efficiency of both targeted and chemotherapy. In phase 1 clinical trials this drug has shown better results. Phase 2 clinical trials are ongoing.

  • MRTX 849

Similarly, MRTX 849 is a small molecule drug. It selectively and irreversibly binds to the KRAS G12C mutated protein and blocks it. This drug also locks the protein in its deactivated form and blocks the cancer progression. This is an oral drug.

Combination therapies in KRAS mutant NSCLC

Instead of using single drugs in KRAS targeted therapy in lung cancer, combinations of two or more drugs have shown better results. This is because of the combined effect against the complex KRAS signalling pathway. For instance, ARS-1620, AMG 510, and MRTX 849 combinatory drugs have enhanced results.

Moreover, ARS-1620 with mTOR and IGF 1R inhibitors give improved effectiveness on KRAS G12C mutant lung cancer in mouse models.

Furthermore, combining AMG 510 with multiple agents such as MEK inhibitors or the traditional chemotherapy drug Carboplatin has shown increased tumour-killing activity. However, these results have been shown in lab testing only.

In addition, AZD4785 is a KRAS antisense oligonucleotide. This can target the KRAS mutant cells without considering their mutational states. AZD4785 showed highly successful preclinical studies in mice and monkeys. It reduces tumour growth significantly. Unfortunately, the drug failed in phase 1 clinical trials.

14. How to find out if you have KRAS positive lung cancer?

Genetic testing of lung cancer

People with lung cancer usually receive treatments like chemotherapy and radiation and surgery, or traditional first-line drugs. However, knowledge on genetics and molecular analysis of cancer genes now has a high impact on lung cancer diagnosis because of targeted therapy-like treatments.

Genetic testing has become a routine of lung cancer diagnosis and staging. Genetic analysis helps to determine further drug prescribing and plan treatments.

Identification of gene mutations in lung cancer

There are new technologies for gene mutation detection at present and they can even identify about 300 genes at once. Samples from the patients are sent to centers or laboratories for analysis. For lung cancer, mainly EGFR, KRAS, and AKL are the common types of mutations present in lung cancer patients.

There are around 60 methods of KRAS gene detection. Among them, certain techniques have shown the best results.

  • Sequencing
  • High resolution melting analysis (HRM)
  • Single-strand conformation polymorphism (SSCP)
  • Denaturing gradient gel electrophoresis (DGGE)
  • Denaturing high-performance liquid chromatography (DHPLC)
  • array/strip analysis
  • Allele-specific PCR is part of the KRAS mutation testing.
Detection methodAdvantagesDisadvantages
Sanger sequencingShows the whole amplifying sequenceNot much sensitive for detection than other methods
High resolution melting analysis (HRM)A useful and quick method for large scale first stage analysisNo DNA sequence detection and low specificity
Single-strand conformation polymorphism, denaturing gradient gel electrophoresisUseful and quick in large scale early-stage analysisNo DNA sequence, low specificity, and a complex process
Array/strip assayThis method has high sensitivity and specificityThis method does not test on KRAS mutation not on the test strip
Allele-specific PCRThis also has high sensitivity and specificityNo DNA sequencing
Table no.01: advantages and disadvantages of different KRAS mutation detection methods. According to the article published on Genes and Cancer in 2012.

15. What is the treatment plan for KRAS mutated lung cancer patients?

At this moment, however various drugs for KRAS targeted therapy for lung cancer have been identified, patients need to get this with other therapies. Basic treatments such as radiotherapy, chemotherapy, and surgery, and immunotherapy, or a combination of these treatments are used by the doctors.

KRAS targeted therapy for lung cancer is still not identified as a single treatment for lung cancer or NSCLC patients. If a person tested positive with KRAS mutation the doctor will decide the best suitable therapy for him. Maybe KRAS targeted therapy included it.

16. Is KRAS targeted therapy for lung cancer an approved treatment?

The U.S.Food and Drug Administration approved the drug Lumakras (sotorasib) for the KRAS targeted therapy for lung cancer recently. This is the first drug that got approval for targeted therapy in any KRAS mutated non-small cell lung cancer patients.

124 patients after getting platinum-based chemotherapy and/or immune checkpoint inhibitors received the drug. These patients were KRAS G12C Non-Small Cell Lung Cancer.

The approved dose of Lumakras is 960mg according to the clinical data. However, these amounts of doses are still under post-marketing evaluation.

Lumakras got the approval using the Accelerated approval pathway of the US FDA. The accelerated approval pathway is for the approval of drugs when the community needs quick medical support or when a drug has shown significant efficacy and safety against a disease.

17. Who produces Lumakras?

The US FDA gave the production right of Lumakras to Amgen Inc.

18. Who can get Lumakras in Kras targeted therapy for lung cancer?

According to the US FDA, adult patients with KRAS G12C mutated non-small cell lung cancer. However, those patients should previously get at least one systemic therapy.

19.Side effects of Kras targeted therapy for lung cancer?

The FDA indicates the possible side effects of a recently approved drug for KRAS targeted therapy for lung cancer, Lumakrs. The most common side effects are

  • Muscle pain
  • Diarrhea
  • Nausea
  • Feeling tired
  • Liver damage
  • Cough

20. Can KRAS mutation be cured and what will be the future of KRAS targeted therapy for lung cancer?

As everything considered, there is no such permanent cure for the KRAS mutated lung cancer. Although advanced research and experiments are ongoing to find new drugs anyone cannot introduce a single treatment for cure.

However, novel drugs are continuously under evaluation and development. New drugs to increase the effectiveness of current drugs and completely new medicines are now in preclinical and early clinical studies.

  • Combination therapies with immune checkpoint inhibitors.
  • Inhibitors of RAS-related pathways like insulin-like growth factor (IGF 1) and mTOR, receptor tyrosine kinases, and PI3K are currently under study and evaluation.
  • PAN KRAS inhibitors are now in the early phases of clinical studies. These can be used as a single therapy or combination with MEK inhibitors.

In summary, everything considered, the future of the KRAS targeted therapy for lung cancer is with promising clinical hopes.

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